Method and device for patient temperature control employing optimized rewarming

ABSTRACT

Embodiments of the invention provide a system for temperature control of the human body. The system includes an indwelling catheter with a tip-mounted heat transfer element. The catheter is fluidically coupled to a console that provides a heated or cooled heat transfer working fluid to exchange heat with the heat transfer element, thereby heating or cooling blood. The heated or cooled blood then heats or cools the patient&#39;s body or a selected portion thereof. In particular, strategies for optimizing the rewarming of patients for various medical procedures are provided, including stroke, neurosurgery, and myocardial infarction.

CONTINUING INFORMATION

This application is a continuation of U.S. patent application Ser. No.11/003,220, filed Dec. 3, 2004, now U.S. Pat. No. 7,351,254, entitled“Method and Device for Patient Temperature Control Employing OptimizedRewarming”, which is a continuation of U.S. patent application Ser. No.10/216,487, entitled “Method And Device For Patient Temperature ControlEmploying Optimized Rewarming”, filed on Aug. 9, 2002, which is acontinuation-in-part of U.S. patent application Ser. Nos. 09/650,940,entitled “Selective Organ Hypothermia Method And Apparatus,” filed onAug. 30, 2000; 09/785,243, entitled “Circulating Fluid HypothermiaMethod And Apparatus,” filed on Feb. 16, 2001; 09/566,531, entitled“Method Of Making Selective Organ Cooling Catheter,” filed on May 8,2000; 09/757,124, entitled “Inflatable Catheter For Selective OrganHeating And Cooling And Method Of Using The Same,” filed on Jan. 8,2001; 09/714,749, entitled “Method For Low Temperature Thrombolysis AndLow Temperature Thrombolytic Agent With Selective Organ TemperatureControl,” filed on Nov. 16, 2000; 09/621,051, entitled “Method AndDevice For Applications Of Selective Organ Cooling,” filed on Jul. 21,2000; 09/800,159, entitled “Method And Apparatus For Location AndTemperature Specific Drug Action Such As Thrombolysis,” filed on Mar. 6,2001; 09/292,532, entitled “Isolated Selective Organ Cooling Method AndApparatus,” filed on Apr. 15, 1999; 09/379,295, entitled “Method OfManufacturing A Heat Transfer Element For In Vivo Cooling,” filed onAug. 23, 1999; 09/885,655, entitled “Inflatable Heat TransferApparatus,” filed on Jun. 20, 2001; 09/246,788, entitled “Method AndDevice For Applications Of Selective Organ Cooling,” filed on Mar. 28,2001; 09/797,028, entitled “Selective Organ Cooling Catheter WithGuidewire Apparatus And Temperature-Monitoring Device,” filed on Feb.27, 2001; 09/607,799, entitled “Selective Organ Cooling Apparatus AndMethod,” filed on Jun. 30, 2000; 09/519,022, entitled “Lumen Design ForCatheter,” filed on Mar. 3, 2000; 10/082,964, entitled “Method ForDetermining The Effective Thermal Mass Of A Body Or Organ Using ACooling Catheter,” filed on Feb. 25, 2002; 09/539,932, entitled “MedicalProcedure,” filed on Mar. 31, 2000; 09/658,950, entitled “MedicalProcedure,” filed on Sep. 11, 2000; 09/373,112, entitled “PatientTemperature Regulation Method And Apparatus,” filed on Aug. 11, 1999;10/007,545, entitled “Circulation Set For Temperature-ControlledCatheter And Method Of Using The Same,” filed on Nov. 6, 2001;10/005,416, entitled “Fever Regulation Method And Apparatus,” filed onNov. 7, 2001; 10/117,733, entitled “Method Of Manufacturing A HeatTransfer Element For In Vivo Cooling,” filed on Apr. 4, 2002, and is aconversion of U.S. Patent Appl. Ser. Nos. 60/311,589, entitled “OptimalRewarming Strategies,” filed on Aug. 9, 2001; 60/312,409, entitled“Controlling The Application Of Hypothermia,” filed on Aug. 15, 2001;60/316,057, entitled “Controlling Hypothermia,” filed on Aug. 29, 2001;60/316,922, entitled “Novel Antishiver Drugs And Regimens,” filed onSep. 31, 2001; 60/322,945, entitled “Novel Antishiver Drugs AndRegimens,” filed on Sep. 14, 2001; 60/328,259, entitled “Single OperatorExchange Coaxially Cooling Catheter,” filed on Oct. 9, 2001; and60/328,320, entitled “Temperature Projection Method In A CatheterMounted Temperature Sensor,” filed on Oct. 9, 2001; all of the above areincorporated by reference herein in their entirety.

FIELD OF THE INVENTION

The present invention relates generally to the lowering, raising, andcontrol of the temperature of the human body. More particularly, theinvention relates to a method and intravascular apparatus forcontrolling the temperature of the human body.

BACKGROUND

Background Information—Organs in the human body, such as the brain,kidney and heart, are maintained at a constant temperature ofapproximately 37° C. Hypothermia can be clinically defined as a corebody temperature of 35° C. or less. Hypothermia is sometimescharacterized further according to its severity. A body core temperaturein the range of 33° C. to 35° C. is described as mild hypothermia. Abody temperature of 28° C. to 32° C. is described as moderatehypothermia. A body core temperature in the range of 24° C. to 28° C. isdescribed as severe hypothermia.

Hypothermia is uniquely effective in reducing ischemia. For example, itis effective in reducing brain injury caused by a variety ofneurological insults and may eventually play an important role inemergency brain resuscitation. Experimental evidence has demonstratedthat cerebral cooling improves outcome after global ischemia, focalischemia, or traumatic brain injury. For this reason, hypothermia may beinduced in order to reduce the effect of certain bodily injuries to thebrain as well as ischemic injuries to other organs.

SUMMARY OF THE INVENTION

The apparatus of the present invention can include a heat transferelement which can be used to apply cooling to the blood flowing in avessel. The heat transfer element, by way of example only, comprisesfirst and second elongated, articulated segments, each segment having aturbulence-inducing exterior surface. A flexible joint can connect thefirst and second elongated segments. An inner coaxial lumen may bedisposed within the first and second elongated segments and is capableof transporting a working fluid to a distal end of the first elongatedsegment. In addition, the first and second elongated segments may have aturbulence-inducing interior surface for inducing turbulence within thepressurized working fluid. The turbulence-inducing exterior surface maybe adapted to induce turbulence within a free stream of blood flow whenplaced within an artery or vein. The turbulence-inducing exteriorsurface may be adapted to induce a turbulence intensity greater than0.05 within a free stream blood flow. In one embodiment, the flexiblejoint comprises a bellows section which also allows for axialcompression of the heat transfer element.

In an embodiment, the turbulence-inducing exterior surfaces of the heattransfer element comprise one or more helical ridges. Adjacent segmentsof the heat transfer element can be oppositely spiraled to increaseturbulence. For instance, the first elongated heat transfer segment maycomprise one or more helical ridges having a counter-clockwise twist,while the second elongated heat transfer segment comprises one or morehelical ridges having a clockwise twist. Alternatively, of course, thefirst elongated heat transfer segment may comprise one or more clockwisehelical ridges, and the second elongated heat transfer segment maycomprise one or more counter-clockwise helical ridges. The first andsecond elongated, articulated segments may be formed from highlyconductive materials.

The heat transfer device may also have a coaxial supply catheter with aninner catheter lumen coupled to the inner coaxial lumen within the firstand second elongated heat transfer segments. A working fluid supplyconfigured to dispense the pressurized working fluid may be coupled tothe inner catheter lumen. The working fluid supply may be configured toproduce the pressurized working fluid at a temperature of about 0° C.and at a pressure below about 5 atmospheres of pressure. The workingfluid may be isolyte, saline, D5W, etc.

In yet another alternative embodiment, the heat transfer device may havethree or more elongated, articulated, heat transfer segments having aturbulence-inducing exterior surface, with additional flexible jointsconnecting the additional elongated heat transfer segments. In one suchembodiment, by way of example, the first and third elongated heattransfer segments may comprise clockwise helical ridges, and the secondelongated heat transfer segment may comprise one or morecounter-clockwise helical ridges. Alternatively, of course, the firstand third elongated heat transfer segments may comprisecounter-clockwise helical ridges, and the second elongated heat transfersegment may comprise one or more clockwise helical ridges.

The turbulence-inducing exterior surface of the heat transfer elementmay optionally include a surface coating or treatment to inhibit clotformation.

The present invention also envisions a method of cooling the body whichcomprises inserting a flexible, conductive cooling element into theinferior vena cava from a distal location, and providing a means ofwarming die body to prevent shivering by means of a cooling blanket. Themethod further includes circulating a working fluid through theflexible, conductive cooling element in order to lower the temperatureof the body. The flexible, conductive heat transfer element absorbs morethan about 25, 50 or 75 Watts of heat.

The method may also comprise inducing turbulence within die free streamblood flow within an artery or vein. In one embodiment, the methodincludes the step of inducing blood turbulence with a turbulenceintensity greater than about 0.05 within the vascular system. Thecirculating may comprise inducing mixing flow of the working fluidthrough the flexible, conductive heat transfer element. The pressure ofthe working fluid may be maintained below about 5 atmospheres ofpressure.

The cooling or warning may comprise circulating a working fluid inthrough an inner lumen in the catheter and out through an outer, coaxiallumen. In one embodiment, the working fluid remains a liquid throughoutthe cycle. The working fluid may be aqueous.

The present invention also envisions a cooling or warming cathetercomprising a catheter shaft having first and second lumens therein. Thecatheter also comprises a cooling or warming tip adapted to transferheat to or from a working fluid circulated in through the first lumenand out through the second lumen, and turbulence-inducing structures onthe tip capable of inducing free stream turbulence when the tip isinserted into a blood vessel. The tip may be adapted to induceturbulence within the working fluid. The catheter is capable of removingat least about 25 Watts of heat from an organ when inserted into avessel supplying that organ, while cooling the tip with a working fluidthat remains a liquid in the catheter. Alternatively, the catheter iscapable of removing at least about 50 or 75 Watts of heat from an organwhen inserted into a vessel supplying that organ, while cooling the tipwith an aqueous working fluid.

In another embodiment, a cooling or warming catheter may comprise acatheter shaft having first and second lumens therein, a cooling orwarming tip adapted to transfer heat to or from a working fluidcirculated in through the first lumen and out through the second lumen,and turbulence-inducing structures on the tip capable of inducingturbulence when the tip is inserted into a blood vessel.

The present invention may also provide a temperature control apparatuscomprising a flexible catheter which can be inserted through thevascular system of a patient to an artery or vein, with an inflatableballoon heat exchanger near the distal end of the catheter. The presentinvention also encompasses a method for using such a device to performcooling, heating, or temperature management. After placement in avessel, an embodiment of the invention includes an apparatus where theheat exchanger balloon is inflated by pressurization with a workingfluid, such as saline, isolyte, D5W, or other similar fluids, orcombinations of these, via a supply lumen in the catheter. The heatexchanger balloon has one or more blood passageways passing through it,from a proximal aspect of the balloon to a distal aspect of the balloon.When the heat exchanger balloon is inflated to contact the wall of theartery in which it is placed, each of the blood passageways comprises atube having an inlet in one face of the heat exchanger balloon and anoutlet in another face of the heat exchanger balloon, thereby allowingblood to continue flowing through the artery after inflation of theballoon. The blood passageway tubes can be constructed of a materialhaving a relatively high thermal conductivity, such as a thin metallizedpolymer, such as a film with one or more metallized surfaces.Alternatively, the blood passageway tubes can be constructed of ametal-loaded polymer film. Further, the entire heat exchanger ballooncan be constructed of such a material, in order to maximize the coolingcapacity of the heat exchanger.

After inflation of the heat exchanger balloon, the saline solution,which is chilled by an external chiller, continues circulating throughthe interior of the heat exchanger balloon, around the blood passagewaytubes, and back out of the balloon through a return lumen in thecatheter. This cools the blood passageway tubes, which in turn cool theblood flowing through them. This cooled blood then flows through theselected organ and cools the organ.

The device can also incorporate a lumen for a guidewire, facilitatingthe navigation of the catheter through the vascular system of thepatient.

In one aspect, the invention is directed to a catheter system to changethe temperature of blood by heat transfer to or from a working fluid.The system includes an inflatable inlet lumen and outlet lumen. Theoutlet lumen is coupled to the inlet lumen so as to transfer workingfluid between the two. The outlet lumen has a structure when inflated toinduce turbulence in the blood and/or in the working fluid.

Variations of the system may include one or more of the following. Theinlet lumen and the outlet lumen may be made of a flexible material suchas latex rubber. The outlet lumen may have a structure to induceturbulence in the working fluid when inflated, such as a helical shapewhich may be tapered in a segmented or non-segmented manner. The radiiof the inlet and outlet lumens may decrease in a distal direction suchthat the inlet and outlet lumens are tapered when inflated. A wire maybe disposed in the inlet or outlet lumens to provide shape and strengthwhen deflated.

The thickness of the outlet lumen, when inflated, may be less than about½ mil. The length of the inlet lumen may be between about 5 and 30centimeters. If the outlet lumen has a helical shape, the diameter ofthe helix may be less than about 8 millimeters when inflated. The outerdiameter of the helix of the outlet lumen, when inflated, may be betweenabout 2 millimeters and 8 millimeters and may taper to between about 1millimeter and 2 millimeters. In segmented embodiments, a length of asegment may be between about 1 centimeter and 10 centimeters. The radiiof the inlet and outlet lumens when inflated may be between about 0.5millimeters and 2 millimeters.

The outlet lumen may further include at least one surface feature and/orinterior feature, the surface feature inducing turbulence in the fluidadjacent the outlet lumen and the interior feature inducing turbulencein the working fluid. The surface feature may include one or morehelical turns or spirals formed in the outlet lumen. Adjacent turns mayemploy opposite helicity. Alternatively or in combination, the surfacefeature may be a series of staggered protrusions formed in the outletlumen.

The turbulence-inducing outlet lumen may be adapted to induce turbulencewhen inflated within a free stream of blood when placed within anartery. The turbulence intensity may be greater than about 0.05. Theturbulence-inducing outlet lumen may be adapted to induce turbulencewhen inflated throughout the period of the cardiac cycle when placedwithin an artery or during at least 20% of the period.

The system may further include a coaxial supply catheter having an innercatheter lumen coupled to the inlet lumen and a working fluid supplyconfigured to dispense the working fluid and having an output coupled tothe inner catheter lumen. The working fluid supply may be configured toproduce a pressurized working fluid at a temperature of between about−3° C. and 36° C. and at a pressure below about 5 atmospheres ofpressure. Higher temperatures may be employed if blood heating isdesired.

The turbulence-inducing outlet lumen may include a surface coating ortreatment such as heparin to inhibit clot formation. A stent may becoupled to the distal end of the inlet lumen. The system may be employedto cool or heat volumes of tissue rather than blood.

In embodiments employing a tapered helical outlet lumen, the taper ofthe outlet lumen allows the outlet lumen to be placed in an arteryhaving a radius less than the first radius. The outlet lumen may betapered in segments. The segments may be separated by joints, the jointshaving a radius less than that of either adjacent segment.

In another aspect, the invention is directed to a method of changing thetemperature of blood by heat transfer. The method includes inserting aninflatable heat transfer element into an artery or vein and inflatingthe same by delivering a working fluid to its interior. The temperatureof the working fluid is generally different from that of the blood. Themethod further includes inducing turbulence in the working fluid bypassing the working fluid through a turbulence-inducing path, such thatturbulence is induced in a substantial portion of a free stream ofblood. The inflatable heat transfer element may have aturbulence-inducing structure when inflated.

In another aspect, the invention is directed towards a method oftreating the brain which includes inserting a flexible heat transferelement into an artery from a distal location and circulating a workingfluid through the flexible heat transfer element to inflate the same andto selectively modify the temperature of an organ without significantlymodifying the temperature of the entire body. The flexible, conductiveheat transfer element preferably absorbs more than about 25, 50 or 75watts of heat. The artery may be the common carotid or a combination ofthe common carotid and the internal carotid.

In another aspect, the invention is directed towards a method forselectively cooling an organ in the body of a patient which includesintroducing a catheter into a blood vessel supplying the organ, thecatheter having a diameter of 5 mm or less, inducing free streamturbulence in blood flowing over the catheter, and cooling the catheterto remove heat from the blood to cool the organ without substantiallycooling the entire body. In one embodiment, the cooling removes at leastabout 75 watts of heat from the blood. In another embodiment the coolingremoves at least about 100 watts of heat from the blood. The organ beingcooled may be the human brain.

The circulating may further include passing the working fluid in throughan inlet lumen and out through an outlet, coaxial lumen. The workingfluid may be a liquid at or well below its boiling point, andfurthermore may be aqueous.

Advantages of the invention include one or more of the following. Thedesign criteria described above for the heat transfer element: smalldiameter when deflated, large diameter when inflated, high flexibility,and enhanced heat transfer rate through increases in the surface of theheat transfer element and the creation of turbulent flow, facilitatecreation of a heat transfer element which successfully achievesselective organ cooling or heating. Because the blood is cooledintravascularly, or in situ, problems associated with externalcirculation of the blood are eliminated. Also, only a single punctureand arterial vessel cannulation are required which may be performed atan easily accessible artery such as the femoral, subclavian, or brachialarteries. By eliminating the use of a cold perfusate, problemsassociated with excessive fluid accumulation are avoided. In addition,rapid cooling to a precise temperature may be achieved. Further,treatment of a patient is not cumbersome and the patient may easilyreceive continued care during the heat transfer process. The device andmethod may be easily combined with other devices and techniques toprovide aggressive multiple therapies. Other advantages will The presentinvention involves a device for heating or cooling a surrounding fluidin a blood vessel that addresses and solves the problems discussedabove. The device includes an elongated catheter body, a heat transferelement located at a distal portion of the catheter body and includingan interior, an elongated supply lumen adapted to deliver a workingfluid to the interior of the heat transfer element and having ahydraulic diameter, an elongated return lumen adapted to return aworking fluid from the interior of the heat transfer element and havinga hydraulic diameter, and wherein the ratio of the hydraulic diameter ofthe return lumen to the hydraulic diameter of the supply lumen issubstantially equal to 0.75.

Implementations of the above aspect of the invention may include one ormore of the following. The supply lumen may be disposed substantiallywithin the return lumen. One of the supply lumen and return lumen mayhave a cross-sectional shape that is substantially luniform. One of thesupply lumen and the return lumen has a cross-sectional shape that issubstantially annular. The supply lumen has a general cross-sectionalshape and the return lumen has a general cross-sectional shape differentfrom the general cross-sectional shape of the supply lumen. The catheterassembly includes an integrated elongated bitumen member having a firstlumen adapted to receive a guide wire and a second lumen comprisingeither the supply lumen or the return lumen. The bi-lumen member has across-sectional shape that is substantially in the shape of a figureeight. The first lumen has a cross-sectional shape that is substantiallycircular and the second lumen has a cross-sectional shape that issubstantially annular. The heat transfer element includes means forinducing mixing in a surrounding fluid. The device further includesmeans for inducing wall jets or means for further enhancing mixing ofthe working fluid to effect further heat transfer between the heattransfer element and working fluid. The heat transfer element includesan interior distal portion and the supply lumen includes first means fordelivering working fluid to the interior distal portion of the heattransfer element and second means for delivering working fluid to theinterior of the heat transfer element at one or more points pointproximal to the distal portion of the heat transfer element.

Another of the invention involves a catheter assembly capable ofinsertion into a selected blood vessel in the vascular system of apatient. The catheter assembly includes an elongated catheter bodyincluding an operative element having an interior at a distal portion ofthe catheter body, an elongated supply lumen adapted to deliver aworking fluid to the interior of the distal portion and having ahydraulic diameter, an elongated return lumen adapted to return aworking fluid from the interior of the operative element and having ahydraulic diameter, and wherein the ratio of the hydraulic diameter ofthe return lumen to the hydraulic diameter of the supply lumen beingsubstantially equal to 0.75.

Any of the implementations described above with respect to one aspect ofthe invention may also apply to other aspects of the invention. Further,implementations of the invention may include one or more of thefollowing. The operative element may include a heat transfer elementadapted to transfer heat to or from the working fluid. The heat transferelement may include means for inducing mixing in a surrounding fluid.The operative element may include a catheter balloon adapted to beinflated with the working fluid.

Another aspect of the invention involves a device for heating or coolinga surrounding fluid in a vascular blood vessel. The device includes anelongated catheter body, a heat transfer element located at a distalportion of the catheter body and including an interior, an integratedelongated bitumen member located within the catheter body and includinga first lumen adapted to receive a guide wire and a second lumen, thesecond lumen comprising either a supply lumen to deliver a working fluidto an interior of the heat transfer element or a return lumen to returna working fluid from the interior of the heat transfer element, and athird lumen comprising either a supply lumen to deliver a working fluidto an interior of the heat transfer element or a return lumen to returna working fluid from the interior of the heat transfer element.

Implementations of the invention may include one or more of thefollowing. The catheter body includes an internal wall and theintegrated bi-lumen member includes an exterior wall, and the thirdlumen is substantially defined by the internal wall of the catheter bodyand the exterior wall of the bitumen member. Both the catheter body andthe bitumen member are extruded. The bitumen member is disposedsubstantially within the third lumen. The second lumen has across-sectional shape that is substantially luniform. The third lumenhas a cross-sectional shape that is substantially annular. The secondlumen has a general cross-sectional shape and the third lumen has ageneral cross-sectional shape different from the general cross-sectionalshape of the second lumen. The bitumen member has a cross-sectionalshape that is substantially in the shape of a figure eight. The firstlumen has a cross-sectional shape that is substantially circular and thesecond lumen has a cross-sectional shape that is substantially luniform.The heat transfer element includes means for inducing mixing in asurrounding fluid. The device further includes means for inducing walljets or means for further enhancing mixing of the working fluid toeffect further heat transfer between the heat transfer element andworking fluid. The heat transfer element includes an interior distalportion and the supply lumen includes first means for delivering workingfluid to the interior distal portion of the heat transfer element andsecond means for delivering working fluid to the interior of the heattransfer element at one or more points point proximal to the distalportion of the heat transfer element.

Another aspect of the present invention involves a catheter assemblycapable of insertion into a selected blood vessel in the vascular systemof a patient. The catheter assembly includes an elongated catheter bodyincluding an operative element having an interior at a distal portion ofthe catheter body, an integrated elongated bitumen member located withinthe catheter body and including a first lumen adapted to receive a guidewire and a second lumen, the second lumen comprising either a supplylumen to deliver a working fluid to the interior of the operativeelement or a return lumen to return a working fluid from the interior ofthe operative element and a third lumen within the catheter body andcomprising either a supply lumen to deliver a working fluid to aninterior of the operative element or a return lumen to return a workingfluid from the interior of the operative element.

Another aspect of the invention involves a method of manufacturing acatheter assembly for heating or cooling a surrounding fluid in a bloodvessel. The method involves extruding an elongated catheter body;locating a heat transfer element including an interior at a distalportion of the catheter body; extruding an integrated elongated bi-lumenmember including a first lumen adapted to receive a guide wire and asecond lumen, the second lumen comprising either a supply lumen todeliver a working fluid to an interior of the heat transfer element or areturn lumen to return a working fluid from the interior of the heattransfer element; and providing the integrated bi-lumen membersubstantially within the elongated catheter body so that a third lumenis formed, the third lumen comprising either a supply lumen to deliver aworking fluid to an interior of the heat transfer element or a returnlumen to return a working fluid from the interior of the heat transferelement.

Implementations of the invention may include one or more of thefollowing. The second lumen has a hydraulic diameter and the third lumenhas a hydraulic diameter, and the ratio of the hydraulic diameter of thesecond lumen to the hydraulic diameter of the third lumen issubstantially equal to 0.75. The step of providing the integratedbitumen member substantially within the elongated catheter body includessimultaneously extruding the integrated bi-lumen member substantiallywithin the elongated catheter body.

Another aspect of the present invention involves a method ofmanufacturing a catheter assembly. The method includes extruding anelongated catheter body; locating an operative element including aninterior at a distal portion of the catheter body; extruding anintegrated elongated bitumen member including a first lumen adapted toreceive a guide wire and a second lumen, the second lumen comprisingeither a supply lumen to deliver a working fluid to an interior of theoperative element or a return lumen to return a working fluid from theinterior of the operative element; and providing the integrated bitumenmember substantially within the elongated catheter body so that a thirdlumen is formed, the third lumen comprising either a supply lumen todeliver a working fluid to an interior of the operative element or areturn lumen to return a working fluid from the interior of theoperative element.

Another aspect of the present invention involves a device for heating orcooling a surrounding fluid in a blood vessel. The device includes anelongated catheter body, a heat transfer element located at a distalportion of the catheter body and including an interior distal portionand an interior portion defining at least a first heat transfer segmentand a second heat transfer segment, and at least one elongated supplylumen located within the catheter body, the at least one elongatedsupply lumen including first means for delivering working fluid to theinterior distal portion of the first heat transfer segment and secondmeans for delivering working fluid to the interior portion of the secondheat transfer segment.

In an implementation of the invention, the second working fluiddelivering means is adapted to deliver working fluid to the interiorportion of the heat transfer element near a midpoint of the heattransfer element.

Another aspect of the present invention involves a device for heating orcooling a surrounding fluid in a blood vessel. The device includes anelongated catheter body, a heat transfer element located at a distalportion of the catheter body and including an interior distal portionand an interior portion, and at least one elongated supply lumen locatedwithin the catheter body, the at least one elongated supply lumenincluding first means for delivering working fluid to the interiordistal portion of the heat transfer element and second means fordelivering working fluid to the interior portion of the heat transferelement at one or more points proximal to the distal portion of the heattransfer element.

In an implementation of the invention, the second working fluiddelivering means is adapted to deliver working fluid to the interiorportion of the heat transfer element near a midpoint of the heattransfer element.

Another aspect of the present invention involves a device for heating orcooling a surrounding fluid in a blood vessel. The device includes anelongated catheter body, a heat transfer element located at a distalportion of the catheter body and including an interior distal portionand an interior portion defining at least a first heat transfer segmentand a second heat transfer segment, a first elongated supply lumenlocated within the catheter body and terminating at the interior distalportion of the heat transfer element into first means for deliveringworking fluid to the interior distal portion of the heat transferelement, and a second elongated supply lumen located within the catheterbody and terminating at a point proximal to the distal portion of theheat transfer element into second means for delivering working fluid tothe interior portion of the heat transfer element at a point proximal tothe distal portion of the heat transfer element.

In an implementation of the invention, the second working fluiddelivering means is adapted to deliver working fluid to the interiorportion of the heat transfer element near a midpoint of the heattransfer element.

Another aspect of the present invention involves a device for heating orcooling a surrounding fluid in a blood vessel. The device includes anelongated catheter body, a heat transfer element located at a distalportion of the catheter body and including an interior distal portionand an interior portion defining at least a first heat transfer segmentinterior portion and a second heat transfer segment interior portion, afirst elongated supply lumen located within the catheter body andterminating at the interior distal portion of the first heat transfersegment into first means for delivering working fluid to the interior ofthe first heat transfer segment, and a second elongated supply lumenlocated within the catheter body and terminating at a point proximal tothe distal portion of the heat transfer element into second means fordelivering working fluid to the interior portion of the second heattransfer segment.

In an implementation of the invention, the second working fluiddelivering means is adapted to deliver working fluid to the interiorportion of the heat transfer element near a midpoint of the heattransfer element.

Another aspect of the present invention involves a device for heating orcooling a surrounding fluid in a blood vessel. The device includes anelongated catheter body, a heat transfer element located at a distalportion of the catheter body and including an interior portion adaptedto induce mixing of a working fluid to effect heat transfer between theheat transfer element and working fluid, the heat transfer elementincluding at least a first heat transfer segment, a second heat transfersegment, and an intermediate segment between the first heat transfersegment and the second heat transfer segment, an elongated supply lumenmember located within the catheter body and adapted to deliver theworking fluid to the interior of the heat transfer element, the supplylumen member including a circular outer surface, an elongated returnlumen defined in part by the outer surface of the supply lumen memberand the interior portion of the heat transfer element and adapted toreturn the working fluid from the interior of the heat transfer element,and wherein the distance between the interior portion of the heattransfer element and the outer surface of the supply lumen memberadjacent the intermediate segment is less than the distance between theinterior portion of the heat transfer element and the outer surface ofthe supply lumen member adjacent the first heat transfer segment.

Implementations of the invention may include one or more of thefollowing. The distance between the interior portion of the heattransfer element and the outer surface of the supply lumen memberadjacent the intermediate segment is such that the characteristic flowresulting from a flow of working fluid is at least of a transitionalnature. The intermediate segment includes an interior diameter that isless than the interior diameter of the first heat transfer segment orthe second heat transfer segment. The supply lumen member includes anouter diameter adjacent the intermediate segment that is greater thanits outer diameter adjacent the first heat transfer segment or thesecond heat transfer segment. The supply lumen member comprises amultiple-lumen member. The supply lumen member includes a supply lumenhaving a hydraulic diameter and the return lumen has a hydraulicdiameter substantially equal to 0.75 the hydraulic diameter of thesupply lumen. The intermediate segment includes a flexible bellowsjoint.

Another aspect of the present invention involves a device for heating orcooling a surrounding fluid in a blood vessel. The device includes anelongated catheter body, a heat transfer element located at a distalportion of the catheter body and including an interior portion adaptedto induce mixing of a working fluid to effect heat transfer between theheat transfer element and working fluid, an elongated supply lumenmember located within the catheter body and adapted to deliver theworking fluid to the interior of the heat transfer element an elongatedreturn lumen member located within the catheter body and adapted toreturn the working fluid from the interior of the heat transfer element,and means located within the heat transfer element for further enhancingmixing of the working fluid to effect further heat transfer between theheat transfer element and working fluid.

Implementations of the invention may include one or more of thefollowing. The supply lumen member comprises a multiple-lumen memberhaving a circular outer surface. The supply lumen member includes asupply lumen having a hydraulic diameter and the return lumen has ahydraulic diameter substantially equal to 0.75 of the hydraulic diameterof the supply lumen.

Another aspect of the present invention involves a device for heating orcooling a surrounding fluid in a blood vessel. The device includes anelongated catheter body, a heat transfer element located at a distalportion of the catheter body and including an interior portion adaptedto induce mixing of a working fluid to effect heat transfer between theheat transfer element and working fluid, an elongated supply lumenmember located within the catheter body and adapted to deliver theworking fluid to the interior of the heat transfer element, an elongatedreturn lumen member located within the catheter body and adapted toreturn the working fluid from the interior of the heat transfer element,and a mixing-enhancing mechanism located within the heat transferelement and adapted to further mix the working fluid to effect furtherheat transfer between the heat transfer element and working fluid.

Implementations of the invention may include one or more of thefollowing. The supply lumen member comprises a multiple-lumen memberhaving a circular outer surface. The supply lumen member includes asupply lumen having a hydraulic diameter and the return lumen has ahydraulic diameter substantially equal to the hydraulic diameter of thesupply lumen.

A fourteenth aspect of the present invention involves a method ofheating or cooling a surrounding fluid in a blood vessel. The methodincludes providing a device for heating or cooling a surrounding fluidin a blood vessel within the blood stream of a blood vessel, the deviceincluding an elongated catheter body, a heat transfer element located ata distal portion of the catheter body and including an interior portionadapted to induce mixing of a working fluid to effect heat transferbetween the heat transfer element and working fluid, an elongated supplylumen member located within the catheter body and adapted to deliver theworking fluid to the interior of the heat transfer element, an elongatedreturn lumen member located within the catheter body and adapted toreturn the working fluid from the interior of the heat transfer element,and a mixing-enhancing mechanism located within the heat transferelement and adapted to further mix the working fluid to effect furtherheat transfer between the heat transfer element and working fluid;causing a working fluid to flow to and along the interior portion of theheat transfer element of the device using the supply lumen and returnlumen; facilitating the transfer of heat between the working fluid andthe heat transfer element by effecting mixing of the working fluid withthe interior portion adapted to induce mixing of a working fluid;facilitating additional transfer of heat between the working fluid andthe heat transfer element by effecting further mixing of the workingfluid with the interior portion with the mixing-enhancing mechanism;causing heat to be transferred between the blood stream and the heattransfer element by the heat transferred between the heat transferelement and working fluid.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of this invention, as well as the invention itself,will be best understood from the attached drawings, taken along with thefollowing description, in which similar reference characters refer tosimilar parts, and in which:

FIG. 1 is a schematic representation of the heat transfer element beingused in an embodiment within the superior vena cava;

FIG. 2 is a graph showing preferential cooling of the high flow organsof the body under a hypothermic therapy; and

FIG. 3 is a graph illustrating the velocity of steady state turbulentflow as a function of time;

FIG. 4 is a graph showing the velocity of the blood flow within anartery as a function of time;

FIG. 5 is a graph illustrating the velocity of steady state turbulentflow under pulsatile conditions as a function of time, similar toarterial blood flow;

FIG. 6 is an elevation view of a turbulence inducing heat transferelement within an artery;

FIG. 7 is a velocity profile diagram showing a typical steady statePoiseuillean flow driven by a constant pressure gradient;

FIG. 8 is a velocity profile diagram showing blood flow velocity withinan artery, averaged over the duration of the cardiac pulse;

FIG. 9 is a velocity profile diagram showing blood flow velocity withinan artery, averaged over the duration of the cardiac pulse, afterinsertion of a smooth heat transfer element within the artery;

FIG. 10 is a schematic diagram of a heat transfer element according toan embodiment of the invention.

FIG. 11 is a graph showing the relationship between the Nusselt number(Nu) and the Reynolds number (Re) for air flowing through a long heatedpipe at uniform wall temperature.

FIG. 12 is an elevation view of one embodiment of a heat transferelement according to the invention;

FIG. 13 is a longitudinal section view of the heat transfer element ofFIG. 1;

FIG. 14 is a transverse section view of the heat transfer element ofFIG. 1;

FIG. 15 is a perspective view of the heat transfer element of FIG. 1 inuse within a blood vessel;

FIG. 16 is a perspective view of another embodiment of a heat transferelement according to the invention, with aligned longitudinal ridges onadjacent segments;

FIG. 17 is a perspective view of another embodiment of a heat transferelement according to the invention, with somewhat offset longitudinalridges on adjacent segments; and

FIG. 18 is a transverse section view of the heat transfer element ofFIG. 16 or FIG. 17.

FIG. 19 is a cut-away perspective view of an alternative embodiment of aheat transfer element according to the invention;

FIG. 20 is a transverse section view of the heat transfer element ofFIG. 5;

FIG. 21 is a front sectional view of a further embodiment of a catheteremploying a heat transfer element according to the principles of theinvention further employing a side-by-side lumen arrangement constructedin accordance with an embodiment of the invention;

FIG. 22 is a cross-sectional view of the catheter of FIG. 21 taken alongline 22-22 of FIG. 21;

FIG. 23 is a front sectional view of a catheter employing a heattransfer element and lumen arrangement constructed in accordance with afurther embodiment of the invention;

FIG. 24 is a front sectional view of a catheter employing a heattransfer element and lumen arrangement constructed in accordance with astill further embodiment of the invention; and

FIG. 25 is a front sectional view of a another embodiment of a catheteremploying a heat transfer element according to the principles of theinvention further employing a side-by-side lumen arrangement constructedin accordance with another embodiment of the invention; and

FIG. 26 is a cross-sectional view of the heat transfer elementillustrated in FIG. 25 taken along line 26-26 of FIG. 25.

FIG. 27 is a side schematic view of an inflatable turbulence-inducingheat transfer element according to an embodiment of the invention, asthe same is disposed within an artery.

FIG. 28 illustrates an inflatable turbulence-inducing heat transferelement according to an alternative embodiment of the inventionemploying a surface area enhancing taper and a turbulence-inducingshape.

FIG. 29 illustrates a tapered joint which may be employed in theembodiment of FIG. 23.

FIG. 30 illustrates a turbulence-inducing heat transfer elementaccording to a second alternative embodiment of the invention employinga surface area enhancing taper and turbulence-inducing surface features.

FIG. 31 illustrates a type of turbulence-inducing surface feature whichmay be employed in the heat transfer element of the embodiment of FIG.28. In FIG. 31 a spiral feature is shown.

FIG. 32 illustrates a heal transfer element according to an alternativeembodiment of the invention employing a surface area enhancing taper.

FIG. 33 illustrates another type of turbulence-inducing surface featurewhich may be employed in the heat transfer element of the embodiment ofFIG. 27. In FIG. 33, a series of staggered protrusions are shown.

FIG. 34 is a transverse cross-sectional view of the heat transferelement of the embodiment of FIG. 33.

FIG. 35 is a perspective view of the device of the present invention inplace in a common carotid artery of a patient;

FIG. 36 is a perspective view of the device shown in FIG. 35, withadditional details of construction;

FIG. 37 is a transverse section view of the device shown in FIG. 36,along the section line 3-3; and

FIG. 38 is a partial longitudinal section view of the device shown inFIG. 30, showing the flow path of the cooling fluid.

FIG. 39 is a schematic representation of the heat transfer element beingused in one embodiment to provide hypothermia to a patient by causingtotal body cooling and then rewarming the body;

FIG. 40 is a schematic representation of the heat transfer element beingused in one embodiment to cool the brain of a patient and to warm theblood returning from the brain in the jugular vein;

FIG. 41 is a schematic representation of the heat transfer element beingused in one embodiment to cool the brain of a patient, while a warmsaline solution is infused to warm the blood returning from the brain inthe jugular vein; and

FIG. 42 is a schematic representation of one embodiment of an externalwarming device which can be used to warm the blood returning from anorgan in a vein.

FIG. 43 is a schematic representation of the heat transfer element beingused in another embodiment to provide hypothermia to a patient bycausing total body cooling and then rewarming the body;

FIG. 44 is a flowchart showing an exemplary method of the inventionemploying heating blankets and thermoregulatory drugs.

FIG. 45 shows a meperidine molecule

FIG. 46 shows a morphine molecule.

FIG. 47 shows a prodine (+) isomer molecule.

FIG. 48 shows a prodine (−) isomer molecule.

FIG. 49 shows a fentanyl molecule.

FIG. 50 shows a hydroxy allyl prodine (+) isomer molecule.

FIG. 51 shows a picenadol (+) isomermolecule.

FIG. 52 shows a picenadol (−) isomer molecule.

FIG. 53 shows a tramadol molecule.

FIG. 54 shows a nefopam molecule.

FIG. 55 is a schematic representation of the use of a heat transferelement to cool the body, according to an embodiment of the invention.

FIG. 56 is a flowchart showing an exemplary method of the invention.

FIG. 57 shows a catheter having a manifold constructed in accordancewith the present invention.

FIG. 58 is an enlarged sectional view of a fragmentary portion of thecatheter shown in FIG. 57.

FIG. 59 is a perspective view of a heat transfer catheter systemincluding a circulation set constructed in accordance with an embodimentof the invention;

FIG. 60 is a cross-sectional view of an embodiment of a distal portionof a heat transfer catheter along with a side-elevational view of anembodiment of a proximal portion of the catheter that may be used withthe circulation set illustrated in FIG. 59;

FIG. 61 is a schematic view of a valve that may be employed in anembodiment of the present invention.

FIG. 62 is a schematic diagram of the circulation set illustrated inFIG. 48;

FIG. 63 is an exploded perspective view of an embodiment of a disposableheat exchanger that may be used in the circulation set of the presentinvention.

FIG. 64 is a cross sectional view of the heat exchanger illustrated inFIG. 52.

FIGS. 65 and 66 are perspective views of the manifold portions of theheat exchanger illustrated in FIG. 63.

FIG. 67 is a perspective view of a temperature and pressure sensorassembly constructed in accordance with an embodiment of the invention;

FIG. 68 is an exploded perspective view of the temperature and pressuresensor assembly illustrated in FIG. 67.

FIG. 69 is an exploded side-elevational view of the temperature andpressure sensor assembly illustrated in FIG. 67.

FIG. 70 is an exploded perspective view of the temperature and pressuresensor assembly illustrated in FIG. 67, but from a different vantagepoint from that of FIG. 68.

FIG. 71 is an exemplary graph of a pump motor speed versus time for apump of the circulation set illustrated in FIG. 59.

FIG. 72 is an exemplary graph of pressure versus pump motor speed for a10 F heat transfer catheter and a 14 F heat transfer catheter used withthe circulation set illustrated in FIG. 59.

FIG. 73 is a schematic representation of layers constituting a wall ofthe heat transfer element according to an embodiment of the inventionand formed by a method according to the invention;

FIG. 74 is a schematic representation of layers constituting a wall ofthe heat transfer element according to a second embodiment of theinvention and formed by a method according to the invention; and

FIG. 75 is an exploded schematic representation of layers constituting awall of the heat transfer element according to a third embodiment of theinvention and formed by a method according to the invention.

DETAILED DESCRIPTION Overview

In the following description, the term “pressure communication” is usedto describe a situation between two points in a flow or in a standingfluid. If pressure is applied at one point, the second point willeventually feel effects of the pressure if the two points are inpressure communication. Any number of valves or elements may be disposedbetween the two points, and the two points may still be in pressurecommunication if the above test is met. For example, for a standingfluid in a pipe, any number of pipe fittings may be disposed between twopipes and, so long as an open path is maintained, points in therespective pipes may still be in pressure communication.

A one or two-step process and a one or two-piece device may be employedto intravascularly lower the temperature of a body in order to inducetherapeutic hypothermia. A cooling element may be placed in a high-flowvein such as the vena cavae to absorb heat from the blood flowing intothe heart. This transfer of heat causes a cooling of the blood flowingthrough the heart and thus throughout the vasculature. Such a method anddevice may therapeutically be used to induce an artificial state ofhypothermia.

A heat transfer element that systemically cools blood should be capableof providing the necessary heat transfer rate to produce the desiredcooling effect throughout the vasculature. This may be up to or greaterthan 300 watts, and is at least partially dependent on the mass of thepatient and the rate of blood flow. Surface features may be employed onthe heat transfer element to enhance the heat transfer rate. The surfacefeatures and other components of the heat transfer element are describedin more detail below.

One problem with hypothermia as a therapy is that the patient'sthermoregulatory defenses initiate, attempting to defeat thehypothermia. Methods and devices may be used to lessen thethermoregulatory response. For example, a heating blanket may cover thepatient. In this way, the patient may be made more comfortable.Thermoregulatory drugs may also be employed to lower the trigger pointat which the patient's thermoregulatory system begins to initiatedefenses. Such drugs are described in more detail below. A methodemploying thermoregulatory drugs, heating blankets, and heat transferelements is also disclosed below.

Anatomical Placement

The internal jugular vein is the vein that directly drains the brain.The external jugular joins the internal jugular at the base of the neck.The internal jugular veins join the subclavian veins to form thebrachiocephalic veins that in turn drain into the superior vena cava.The superior vena cava drains into the right atrium of the heart as maybe seen by referring ahead to FIG. 1. The superior vena cava suppliesblood to the heart from the upper part of the body.

A cooling element may be placed into the superior vena cava, inferiorvena cava, or otherwise into a vein which feeds into the superior venacava or otherwise into the heart to cool the body. A physicianpercutaneously places the catheter into the subclavian or internal orexternal jugular veins to access the superior vena cava. The blood,cooled by the heat transfer element, may be processed by the heart andprovided to the body in oxygenated form to be used as a conductivemedium to cool the body. The lungs have a fairly low heat capacity, andthus the lungs do not cause appreciable rewarming of the flowing blood.

The vasculature by its very nature provides preferential blood flow tothe high blood flow organs such as the brain and the heart. Thus, theseorgans are preferentially cooled by such a procedure as is also shownexperimentally in FIG. 2. FIG. 2 is a graph of measured temperatureplotted versus cooling time. This graph show the effect of placing acooling element in the superior vena cavae of a sheep. The core bodytemperature as measured by an esophageal probe is shown by curve 14. Thebrain temperature is shown by curve 12. The brain temperature is seento-decrease more rapidly than the core body temperature throughout theexperiment. The inventors believe this effect to be due to thepreferential supply of blood provided to the brain and heart. Thiseffect may be even more pronounced if thermoregulatory effects, such asvasoconstriction, occur that tend to focus blood supply to the corevascular system and away from the peripheral vascular system.

Heat Transfer

When a heat transfer element is inserted approximately coaxially into anartery or vein, the primary mechanism of heat transfer between thesurface of the heat transfer element and the blood is forced convection.Convection relies upon the movement of fluid to transfer heat. Forcedconvection results when an external force causes motion within thefluid. In the case of arterial or venous flow, the beating heart causesthe motion of the blood around the heat transfer element.

The magnitude of the heat transfer rate is proportional to the surfacearea of the heat transfer element, the temperature differential, and theheat transfer coefficient of the heat transfer element.

The receiving artery or vein into which the heat transfer element isplaced has a limited diameter and length. Thus, the surface area of theheat transfer element must be limited to avoid significant obstructionof the artery or vein and to allow the heat transfer element to easilypass through the vascular system. For placement within the superior venacava via the external jugular, the cross sectional diameter of the heattransfer element may be limited to about 5-6 mm, and its length may belimited to approximately 10-15 cm. For placement within the inferiorvena cava, the cross sectional diameter of the heat transfer element maybe limited to about 6-7 mm, and its length may be limited toapproximately 25-35 cm.

Decreasing the surface temperature of the heat transfer element canincrease the temperature differential. However, the minimum allowablesurface temperature is limited by the characteristics of blood. Bloodfreezes at approximately 0° C. When the blood approaches freezing, iceemboli may form in the blood, which may lodge downstream, causingserious ischemic injury. Furthermore, reducing the temperature of theblood also increases its viscosity, which results in a small decrease inthe value of the convection heat transfer coefficient. In addition,increased viscosity of the blood may result in an increase in thepressure drop within the artery, thus compromising the flow of blood tothe brain. Given the above constraints, it is advantageous to limit theminimum allowable surface temperature of the cooling element toapproximately 5° C. This results in a maximum temperature differentialbetween the blood stream and the cooling element of approximately 32° C.For other physiological reasons, there are limits on the maximumallowable surface temperature of the warming element.

The mechanisms by which the value of the convection heat transfercoefficient may be increased are complex. However, it is well known thatthe convection heat transfer coefficient increases with the level of“mixing” or “turbulent” kinetic energy in the fluid flow. Thus it isadvantageous to have blood flow with a high degree of mixing in contactwith the heat transfer element.

The blood flow has a considerably more stable flux in the superior venacava than in an artery. However, the blood flow in the superior venacava still has a high degree of inherent mixing or turbulence. Reynoldsnumbers in the superior vena cava may range, for example, from 2,000 to5,000. Thus, blood cooling in the superior vena cava may benefit fromenhancing the level of mixing with the heat transfer element but thisbenefit may be substantially less than that caused by the inherentmixing.

A thin boundary layer has been shown to form during the cardiac cycle.Boundary layers develop adjacent to the heat transfer element as well asnext to the walls of the artery or vein. Each of these boundary layershas approximately the same thickness as the boundary layer that wouldhave developed at the wall of the artery in the absence of the heattransfer element. The free stream flow region is developed in an annularring around the heat transfer element. The heat transfer element used insuch a vessel should reduce the formation of such viscous boundarylayers.

Heat Transfer Element Chap Characteristics

The intravascular heat transfer element should be flexible in order tobe placed within the vena cavae or other veins or arteries. Theflexibility of the heat transfer element is an important characteristicbecause the same is typically inserted into a vein such as the externaljugular and accesses the superior vena cava by initially passing thougha series of one or more branches. Further, the heat transfer element isideally constructed from a highly thermally conductive material such asmetal in order to facilitate heat transfer. The use of a highlythermally conductive material increases the heat transfer rate for agiven temperature differential between the working fluid within the heattransfer element and the blood. This facilitates the use of a highertemperature coolant, or lower temperature warming fluid, within the heattransfer element, allowing safer working fluids, such as water orsaline, to be used. Highly thermally conductive materials, such asmetals, tend to be rigid. Therefore, the design of the heat transferelement should facilitate flexibility in an inherently inflexiblematerial.

It is estimated that the cooling element should absorb at least about300 Watts of heat when placed in the superior vena cava to lower thetemperature of the body to between about 30° C. and 34° C. Thesetemperatures are thought to be appropriate to obtain the benefits ofhypothermia described above. The power removed determines how quicklythe target temperature can be reached. For example, in a stroke therapyin which it is desired to lower brain temperature, the same may belowered about 4° C. per hour in a 70 kg human upon removal of 300 Watts.

One embodiment of the invention uses a modular design. This designcreates helical blood flow and produces a level of mixing in the bloodflow by periodically forcing abrupt changes in the direction of thehelical blood flow. The abrupt changes in flow direction are achievedthrough the use of a series of two or more heat transfer segments, eachincluded of one or more helical ridges. The use of periodic abruptchanges in the helical direction of the blood flow in order to inducestrong free stream turbulence may be illustrated with reference to acommon clothes washing machine. The rotor of a washing machine spinsinitially in one direction causing laminar flow. When the rotor abruptlyreverses direction, significant turbulent kinetic energy is createdwithin the entire wash basin as the changing currents cause randomturbulent motion within the clothes-water slurry. These surface featuresalso tend to increase the surface area of the heat transfer element,further enhancing heat transfer.

A heat transfer element with a smooth exterior surface may be able toprovide the desired amount of heat transfer. However, as noted above, itis well known that the convection heat transfer coefficient increaseswith the level of turbulent kinetic energy in the fluid flow. Thus, ifflow past a smooth heat transfer element will not transfer sufficientheat, it is advantageous to have turbulent or otherwise mixed blood flowin contact with the heat transfer element.

FIG. 3 is a graph illustrating steady state turbulent flow. The verticalaxis is the velocity of the flow. The horizontal axis represents time.The average velocity of the turbulent flow is shown by a line 118. Theactual instantaneous velocity of the flow is shown by a curve 116.

Under constant pressure conditions, steady flows in pipes arecharacterized as a balance between viscous stresses and the constantpressure gradient. Such flows are called Poiseuillean. FIG. 7 is avelocity profile diagram showing a typical steady state Poiseuilleanflow driven by a constant pressure gradient. The velocity of the fluidacross the pipe is shown in FIG. 7 by the parabolic curve andcorresponding velocity vectors. The velocity of the fluid in contactwith the wall of the pipe is zero. The boundary layer is the region ofthe flow in contact with the pipe surface in which viscous stresses aredominant. In steady state Poiseuillean flow, the boundary layer developsuntil it includes the whole pipe, i.e., the boundary layer thickness inFIG. 16 is one half of the diameter of the pipe.

Under conditions of Poiseuillean flow, the Reynolds number, the ratio ofinertial forces to viscous forces, can be used to characterize the levelof turbulent kinetic energy existing in the flow. For Poiseuilleanflows, Reynolds numbers must be greater than about 2300 to cause atransition from laminar to turbulent flow. Further, when the Reynoldsnumber is greater than about 2000, the boundary layer is receptive to“tripping”. Tripping is a process by which a small perturbation in theboundary layer can create turbulent conditions. The receptivity of aboundary layer to “tripping” is proportional to the Reynolds number andis nearly zero for Reynolds numbers less than 2000.

In contrast with the steady Poiseuillean flow, the blood flow inarteries is induced by the beating heart and is therefore pulsatile. Thebelow description of this pulsatile flow, referring to FIGS. 5-19, thusdescribes the situation when a heat transfer element is inserted into anartery. FIG. 4 is a graph showing the velocity of the blood flow withinan artery as a function of time. The beating heart provides pulsatileflow with an approximate period of 0.5 to 1 second. This is known as theperiod of the cardiac cycle. The horizontal axis in FIG. 4 representstime in seconds and the vertical axis represents the average velocity ofblood in centimeters per second. Although very high velocities arereached at the peak of the pulse, the high velocity occurs for only asmall portion of the cycle. In fact, the velocity of the blood reacheszero in the carotid artery at the end of a pulse and temporarilyreverses.

Because of the relatively short duration of the cardiac pulse, the bloodflow in the arteries does not develop into the classic Poiseuilleanflow. FIG. 8 is a velocity profile diagram showing blood flow velocitywithin an artery averaged over the cardiac pulse. The majority of theflow within the artery has the same velocity. The boundary layer wherethe flow velocity decays from the free stream value to zero is verythin, typically ⅙ to 1/20 of the diameter of the artery, as opposed toone half of the diameter of the artery in the Poiseuillean flowcondition.

As noted above, if the flow in the artery were steady rather thanpulsatile, the transition from laminar to turbulent flow would occurwhen the value of the Reynolds number exceeds about 2,000. However, inthe pulsatile arterial flow, the value of the Reynolds number variesduring the cardiac cycle, just as the flow velocity varies. In pulsatileflows, due to the enhanced stability associated with the acceleration ofthe free stream flow, the critical value of the Reynolds number at whichthe unstable modes of motion grow into turbulence is found to be muchhigher, perhaps as high as 9,000.

The blood flow in the arteries of interest remains laminar over morethan 80% of the cardiac cycle. Referring again to FIG. 4, the blood flowis turbulent from approximately time t₁ until time t₂ during a smallportion of the descending systolic flow, which is less than 20% of theperiod of the cardiac cycle. If a heat transfer element is placed insidethe artery, heat transfer will be facilitated during this shortinterval. However, to transfer the necessary heat to selectively coolthe brain, in arterial embodiments, turbulent kinetic energy should beproduced in the blood stream and sustained throughout the entire periodof the cardiac cycle.

A thin boundary layer has been shown to form during the cardiac cycle.This boundary layer will form over the surface of a smooth heat transferelement. FIG. 9 is a velocity profile diagram showing blood flowvelocity within an artery, averaged over the cardiac pulse, afterinsertion of a smooth heat transfer element within the artery. In FIG.9, the diameter of the heat transfer element is about one half of thediameter of the artery. Boundary layers develop adjacent to the heattransfer element as well as next to the walls of the artery. Each ofthese boundary layers has approximately the same thickness as theboundary layer which would have developed at the wall of the artery inthe absence of the heat transfer element. The free stream flow region isdeveloped in an annular ring around the heat transfer element. Bloodflow past such a smooth heat transfer element may transfer sufficientheat to accomplish the desired temperature control.

One way to increase the heat transfer rate is to create a turbulentboundary layer on the heat transfer element surface. However, turbulencein the very thin boundary layer will not produce sufficient kineticenergy to produce the necessary heat transfer rate. Therefore, to inducesufficient turbulent kinetic energy to increase the heat transfer ratesufficiently to cool the brain, a stirring mechanism, which abruptlychanges the direction of velocity vectors, should be utilized. This cancreate high levels of turbulence intensity in the free stream, therebysufficiently increasing the heat transfer rate.

This turbulence intensity should ideally be sustained for a significantportion of the cardiac cycle. Further, turbulent kinetic energy shouldideally be created throughout the free stream and not just in theboundary layer. FIG. 5 is a graph illustrating the velocity ofcontinually turbulent flow under pulsatile conditions as a function oftime, which would result in optimal heat transfer in arterial bloodflow. Turbulent velocity fluctuations are seen throughout the cycle asopposed to the short interval of fluctuations seen in FIG. 4 betweentime t₁ and time t₂. These velocity fluctuations are found within thefree stream. The turbulence intensity shown in FIG. 5 is at least 0.05.In other words, the instantaneous velocity fluctuations deviate from themean velocity by at least 5%. Although, ideally, turbulence or mixing iscreated throughout the entire period of the cardiac cycle, the benefitsof turbulence are also obtained if the turbulence or mixing is sustainedfor only 75%, 50% or even as low as 30% or 20% of the cardiac cycle.

To create the desired level of turbulence intensity or mixing in theblood free stream during the whole cardiac cycle, one embodiment of theinvention uses a modular design. This design creates helical blood flowand produces a high level of mixing in the free stream.

For a swirling flow in a tube in which the azimuthal velocity of thefluid vanishes toward the stationary outer boundary, any non-vanishingazimuthal velocity in the interior of the flow will result in aninstability in which the inner fluid is spontaneously exchanged withfluid near the wall, analogous to Taylor cells in the purely azimuthalflow between a rotating inner cylinder and stationary outer cylinder.This instability results from the lack of any force in opposition to thecentripetal acceleration of the fluid particles moving along helicalpaths, the pressure in the tube being a function only of longitudinalposition. In one embodiment, the device of the present invention impartsan azimuthal velocity to the interior of a developed pipe flow, with thenet result being a continuous exchange of fluid between the core andperimeter of the flow as it moves longitudinally down the pipe. Thisfluid exchange enhances the transport of heat, effectively increasingthe convective heat transfer coefficient over that which would haveobtained in undisturbed pipe flow. This bulk exchange of fluid is notnecessarily turbulent, although turbulence is possible if the inducedazimuthal velocity is sufficiently high.

FIG. 6 is a perspective view of such a turbulence inducing ormixing-inducing heat transfer element within an artery. In thisembodiment, turbulence or mixing is further enhanced by periodicallyforcing abrupt changes in the direction of the helical blood flow.Turbulent or mixed flow would be found at point 120, in the free streamarea. The abrupt changes in flow direction are achieved through the useof a series of two or more heat transfer segments, each comprised of oneor more helical ridges. Ideally, the segments will be close enoughtogether to prevent re-laminarization of the flow in between segments.

The use of periodic abrupt changes in the helical direction of the bloodflow in order to induce strong free stream turbulence or mixing may beillustrated with reference to a common clothes washing machine. Therotor of a washing machine spins initially in one direction causinglaminar flow. When the rotor abruptly reverses direction, significantturbulent kinetic energy is created within the entire wash basin as thechanging currents cause random turbulent mixing motion within theclothes-water slurry.

A device according to an embodiment of the invention for accomplishingsuch cooling or heating is shown schematically in FIG. 10, which shows avessel wall 132 in which a blood flow 100 is passing. A catheter 130 isdisposed within the blood flow 100 to affect the blood temperature.Catheter 101 has an inlet lumen 126 for providing a working fluid 107and an outlet lumen 124 for draining the working fluid 128. Thefunctions of the respective lumens may of course be opposite to thatstated. A reverse configuration may be particularly advantageous whenblood heating, rather than blood cooling, is the objective.

Heat transfer in this system is governed by the following mechanisms:

convective heat transfer from the blood 122 to the outlet lumen 124;conduction through the wall of the outlet lumen 124;convective heat transfer from the outlet lumen 124 to the working fluid128;conduction through the working fluid 128;convective heat transfer from working fluid 128 in the outlet lumen 124to the inlet lumen 126; andconduction through the wall of the inlet lumen 126.

Once the materials for the lumens and the working fluid are chosen, theconductive heat transfers are solely dependent on the temperaturegradients. Convective heat transfers, by contrast, also rely on themovement of fluid to transfer heat. Forced convection results when theheat transfer surface is in contact with a fluid whose motion is induced(or forced) by a pressure gradient, area variation, or other such force.In the case of arterial flow, the beating heart provides an oscillatorypressure gradient to force the motion of the blood in contact with theheat transfer surface. One of the aspects of the device uses turbulenceto enhance this forced convective heat transfer.

The rate of convective heat transfer Q is proportional to the product ofS, the area of the heat transfer element in direct contact with thefluid, ΔT=T_(b)−T_(s), the temperature differential between the surfacetemperature T_(s) of the heat transfer element and the free stream bloodtemperature T_(b), and h_(c) , the average convection heat transfercoefficient over the heat transfer area. h_(c) is sometimes called the“surface coefficient of heat transfer” or the “convection heat transfercoefficient”.

The magnitude of the heat transfer rate Q to or from the fluid flow canbe increased through manipulation of the above three parameters.Practical constraints limit the value of these parameters and how muchthey can be manipulated. For example, the internal diameter of thecommon carotid artery ranges from 6 to 8 mm. Thus, the heat transferelement residing therein may not be much larger than 4 mm in diameter toavoid occluding the vessel. The length of the heat transfer elementshould also be limited. For placement within the internal and commoncarotid artery, the length of the heat transfer element is limited toabout 10 cm. This estimate is based on the length of the common carotidartery, which ranges from 8 to 12 cm. Embodiments intended for use inthe venous system would be analyzed similarly.

Consequently, the value of the surface area S is limited by the physicalconstraints imposed by the size of the artery into which the device isplaced. Surface features, such as fins, can be used to increase thesurface area of the heat transfer element, however, these features alonecannot usually provide enough surface area enhancement to meet therequired heat transfer rate. An embodiment of the device described belowprovides a tapered heat transfer element which employs a large surfacearea but which may advantageously fit into small arteries and veins. Asthe device is inflatable, the same may be inserted in relatively smallarteries and veins in a deflated state, allowing a minimally invasiveentry. When the device is in position, the same may be inflated,allowing a large surface area and thus an enhanced heat transfer rate.

One may also attempt to vary the magnitude of the heat transfer rate byvarying ΔT. The value of ΔT=T_(b)−T_(s) can be varied by varying thesurface temperature T_(s) of the heat transfer element. The allowablesurface temperature of the heat transfer element is limited by thecharacteristics of blood. The blood temperature is fixed at about 37°C., and blood freezes at approximately 0° C. When the blood approachesfreezing, ice emboli may form in the blood which may lodge downstream,causing serious ischemic injury. Furthermore, reducing the temperatureof the blood also increases its viscosity which results in a smalldecrease in the value of h_(c) . Increased viscosity of the blood mayfurther result in an increase in the pressure drop within the vessel,thus compromising the flow of blood. Given the above constraints, it isadvantageous to limit the surface temperature of the heat transferelement to approximately 1° C.-5° C., thus resulting in a maximumtemperature differential between the blood stream and the heat transferelement of approximately 32° C.-36° C.

One may also attempt to vary the magnitude of the heat transfer rate byvarying h_(c) . Fewer constraints are imposed on the value of theconvection heat transfer coefficient h_(c) . The mechanisms by which thevalue of h_(c) may be increased are complex. However, one way toincrease h_(c) for a fixed mean value of the velocity is to increase thelevel of turbulent kinetic energy in the fluid flow.

The heat transfer rate Q_(no-flow) in the absence of fluid flow isproportional to ΔT, the temperature differential between the surfacetemperature T_(s) of the heat transfer element and the free stream bloodtemperature T_(b) times k, the diffusion constant, and is inverselyproportion to δ, the thickness of the boundary layer.

The magnitude of the enhancement in heat transfer by fluid flow can beestimated by taking the ratio of the heat transfer rate with fluid flowto the heat transfer rate in the absence of fluid flowN=Q_(flow)/Q_(no-flow)= h_(c) /(k/δ). This ratio is called the Nusseltnumber (“Nu”). For convective heat transfer between blood and thesurface of the heat transfer element, Nusselt numbers of 30-80 have beenfound to be appropriate for selective cooling applications of variousorgans in the human body. Nusselt numbers are generally dependent onseveral other numbers: the Reynolds number, the Womersley number, andthe Prandtl number.

Stirring-type mechanisms, which abruptly change the direction ofvelocity vectors, may be utilized to induce turbulent kinetic energy andincrease the heat transfer rate. The level of turbulence so created ischaracterized by the turbulence intensity l. Turbulence intensity l isdefined as the root mean square of the fluctuating velocity divided bythe mean velocity. Such mechanisms can create high levels of turbulenceintensity in the free stream, thereby increasing the heat transfer rate.This turbulence intensity should ideally be sustained for a significantportion of the cardiac cycle, and should ideally be created throughoutthe free stream and not just in the boundary layer.

Turbulence does occur for a short period in the cardiac cycle anyway. Inparticular, the blood flow is turbulent during a small portion of thedescending systolic flow. This portion is less than 20% of the period ofthe cardiac cycle. If a heat transfer element is placed co-axiallyinside the artery, the heat transfer rate will be enhanced during thisshort interval. For typical of these fluctuations, the turbulenceintensity is at least 0.05. In other words, the instantaneous velocityfluctuations deviate from the mean velocity by at least 5%. Althoughideally turbulence is created throughout the entire period of thecardiac cycle, the benefits of turbulence are obtained if the turbulenceis sustained for 75%, 50% or even as low as 30% or 20% of the cardiaccycle.

One type of turbulence-inducing heat transfer element which may beadvantageously employed to provide heating or cooling of an organ orvolume is described in U.S. Pat. No. 6,096,068 to Dobak and Lasheras fora “Selective Organ Cooling Catheter and Method of Using the Same,”incorporated by reference above. In that application, the heat transferelement is made of a high thermal conductivity material, such as metal.The metal heat transfer element provides a high degree of heat transferdue to its high thermal conductivity. In that application, bellowsprovided a high degree of articulation that compensated for theintrinsic stiffness of the metal. The device size was minimized, e.g.,less than 4 mm, to prevent blockage of the blood flowing in the artery.

FIG. 11 illustrates the dependency of the Nusselt number on the Reynoldsnumber for a fluid flowing through a long duct, i.e., air flowing thougha long heated pipe at a uniform wall temperature. Although FIG. 11illustrates this relationship for a different fluid through a differentstructure, the inventors of the present invention believe a similarrelationship exists for blood flow through a blood vessel. FIG. 11illustrates that flow is laminar when the Reynolds number is below somenumber, in this case about 2100. In the range of Reynolds numbersbetween another set of numbers, in this case 2100 and 10,000, atransition from laminar to turbulent flow takes place. The flow in thisregime is called transitional. The mixing caused by the heat transferelement of the present invention produces a flow that is at leasttransitional. At another Reynolds number, in the case above, about10,000, the flow becomes fully turbulent.

The type of flow that occurs is important because in laminar flowthrough a duct, there is no mixing of warmer and colder fluid particlesby eddy motion. Thus, the only heat transfer that takes place is throughconduction. Since most fluids have small thermal conductivities, theheat transfer coefficients in laminar flow are relatively small. Intransitional and turbulent flow, mixing occurs through eddies that carrywarmer fluid into cooler regions and vice versa. Since the mixingmotion, even if it is only on a small scale compared to fully turbulentflow, accelerates the transfer of heat considerably, a marked increasein the heat transfer coefficient occurs above a certain Reynolds number,which in the graph of FIG. 11 is about 2100. It can be seen from FIG. 11that it is at approximately this point where the Nusselt numberincreases more dramatically. A different set of numbers may be measuredfor blood flow through an artery or vein. However, the inventors believethat a Nusselt number at least in the transitional region is importantfor enhanced heat transfer.

Device

FIG. 12 is an elevation view of one embodiment of a cooling element 102according to the present invention. The heat transfer element 102includes a series of elongated, articulated segments or modules134,104,106. Three such segments are shown in this embodiment, but twoor more such segments could be used without departing from the spirit ofthe invention. As seen in FIG. 12, a first elongated heat transfersegment 134 is located at the proximal end of the heat transfer element102. A mixing-inducing exterior surface of the segment 134 includes fourparallel helical ridges 138 with four parallel helical grooves 136therebetween. One, two, three, or more parallel helical ridges 138 couldalso be used without departing from the spirit of the present invention.In this embodiment, the helical ridges 138 and the helical grooves 136of the heat transfer segment 134 have a left hand twist, referred toherein as a counter-clockwise spiral or helical rotation, as theyproceed toward the distal end of the heat transfer segment 134.

The first heat transfer segment 134 is coupled to a second elongatedheat transfer segment 104 by a first bellows section 140, which providesflexibility and compressibility. The second heat transfer segment 104includes one or more helical ridges 144 with one or more helical grooves142 therebetween. The ridges 144 and grooves 142 have a right band, orclockwise, twist as they proceed toward the distal end of the heattransfer segment 104. The second heat transfer segment 104 is coupled toa third elongated heat transfer segment 106 by a second bellows section108. The third heat transfer segment 106 includes one or more helicalridges 148 with one or more helical grooves 146 therebetween. Thehelical ridge 148 and the helical groove 146 have a left hand, orcounter-clockwise, twist as they proceed toward the distal end of theheat transfer segment 106. Thus, successive heat transfer segments 134,104, 106 of the heat transfer element 102 alternate between havingclockwise and counterclockwise helical twists. The actual left or righthand twist of any particular segment is immaterial, as long as adjacentsegments have opposite helical twist.

In addition, the rounded contours of the ridges 138, 144, 148 allow theheat transfer element 102 to maintain a relatively atraumatic profile,thereby minimizing the possibility of damage to the blood vessel wall. Aheat transfer element according to the present invention may includetwo, three, or more heat transfer segments.

The bellows sections 140, 108 are formed from seamless and nonporousmaterials, such as metal, and therefore are impermeable to gas, whichcan be particularly important, depending on the type of working fluidthat is cycled through the heat transfer element 102. The structure ofthe bellows sections 140, 108 allows them to bend, extend and compress,which increases the flexibility of the heat transfer element 102 so thatit is more readily able to navigate through blood vessels. The bellowssections 140, 108 also provide for axial compression of the heattransfer element 102, which can limit the trauma when the distal end ofthe heat transfer element 102 abuts a blood vessel wall. The bellowssections 140, 108 are also able to tolerate cryogenic temperatureswithout a loss of performance. In alternative embodiments, the bellowsmay be replaced by flexible polymer tubes, which are bonded betweenadjacent heat transfer segments.

The exterior surfaces of the heat transfer element 102 can be made frommetal, and may include very high thermal conductivity materials such asnickel, thereby facilitating heat transfer. Alternatively, other metalssuch as stainless steel, titanium, aluminum, silver, copper and thelike, can be used, with or without an appropriate coating or treatmentto enhance biocompatibility or inhibit clot formation. Suitablebiocompatible coatings include, e.g., gold, platinum or polymerparalyene. The heat transfer element 102 may be manufactured by platinga thin layer of metal on a mandrel that has the appropriate pattern. Inthis way, the heat transfer element 102 may be manufacturedinexpensively in large quantities, which is an important feature in adisposable medical device.

Because the heat transfer element 102 may dwell within the blood vesselfor extended periods of time, such as 24-48 hours or even longer, it maybe desirable to treat the surfaces of the heat transfer element 102 toavoid clot formation. In particular, one may wish to treat the bellowssections 140, 108 because stagnation of the blood flow may occur in theconvolutions, thus allowing clots to form and cling to the surface toform a thrombus. One means by which to prevent thrombus formation is tobind an antithrombogenic agent to the surface of the heat transferelement 102. For example, heparin is known to inhibit clot formation andis also known to be useful as a biocoating. Alternatively, the surfacesof the heat transfer element 102 may be bombarded with ions such asnitrogen. Bombardment with nitrogen can harden and smooth the surfaceand thus prevent adherence of clotting factors. Another coating thatprovides beneficial properties may be a lubricious coating. Lubriciouscoatings, on both the heat transfer element and its associated catheter,allow for easier placement in the, e.g., vena cava.

FIG. 13 is a longitudinal sectional view of the heat transfer element102 of an embodiment of the invention, taken along line 2-2 in FIG. 12.Some interior contours are omitted for purposes of clarity. An innertube 150 creates an inner lumen 158 and an outer lumen 156 within theheat transfer element 102. Once the heat transfer element 102 is inplace in the blood vessel, a working fluid such as saline or otheraqueous solution may be circulated through the heat transfer element102. Fluid flows up a supply catheter into the inner lumen 158. At thedistal end of the heat transfer element 102, the working fluid exits theinner lumen 158 and enters the outer lumen 156. As the working fluidflows through the outer lumen 156, heat is transferred from the workingfluid to the exterior surface 152 of the heat transfer element 102.Because the heat transfer element 102 is constructed from a highconductivity material, the temperature of its exterior surface 152 mayreach very close to the temperature of the working fluid. The tube 150may be formed as an insulating divider to thermally separate the innerlumen 158 from the outer lumen 156. For example, insulation may beachieved by creating longitudinal air channels in the wall of theinsulating tube 150. Alternatively, the insulating tube 150 may beconstructed of a non-thermally conductive material likepolytetrafluoroethylene or another polymer.

It is important to note that the same mechanisms that govern the heattransfer rate between the exterior surface 152 of the heat transferelement 102 and the blood also govern the heat transfer rate between theworking fluid and the interior surface 154 of the heat transfer element102. The heat transfer characteristics of the interior surface 154 areparticularly important when using water, saline or other fluid thatremains a liquid as the working fluid. Other coolants such as Freonundergo nucleate boiling and create mixing through a differentmechanism. Saline is a safe working fluid, because it is non-toxic, andleakage of saline does not result in a gas embolism, which could occurwith the use of boiling refrigerants. Since mixing in the working fluidis enhanced by the shape of the interior surface 154 of the heattransfer element 102, the working fluid can be delivered to the coolingelement 102 at a warmer temperature and still achieve the necessarycooling rate. Similarly, since mixing in the working fluid is enhancedby the shape of the interior surface of the heat transfer element, theworking fluid can be delivered to the warming element 102 at a coolertemperature and still achieve the necessary warming rate.

This has a number of beneficial implications in the need for insulationalong the catheter shaft length. Due to the decreased need forinsulation, the catheter shaft diameter can be made smaller. Theenhanced heat transfer characteristics of the interior surface of theheat transfer element 102 also allow the working fluid to be deliveredto the heat transfer element 102 at lower flow rates and lowerpressures. High pressures may make the heat transfer element stiff andcause it to push against the wall of the blood vessel, thereby shieldingpart of the exterior surface 152 of the heat transfer element 102 fromthe blood. Because of the increased heat transfer characteristicsachieved by the alternating helical ridges 138, 144, 148, the pressureof the working fluid may be as low as 5 atmospheres, 3 atmospheres, 2atmospheres or even less than 1 atmosphere.

FIG. 14 is a transverse sectional view of the heat transfer element 102of the invention, taken at a location denoted by the line 3-3 in FIG.12. FIG. 14 illustrates a five-lobed embodiment, whereas FIG. 12illustrates a four-lobed embodiment. As mentioned earlier, any number oflobes might be used. In FIG. 14, the construction of the heat transferelement 102 is clearly shown. The inner lumen 158 is defined by theinsulating tube 150. The outer lumen 156 is defined by the exteriorsurface of the insulating tube 150 and the interior surface 154 of theheat transfer element 102. In addition, the helical ridges 144 andhelical grooves 142 may be seen in FIG. 14. Although FIG. 14 shows fourridges and four grooves, the number of ridges and grooves may vary.Thus, heat transfer elements with 1, 2, 3, 4, 5, 6, 7, 8 or more ridgesare specifically contemplated.

FIG. 15 is a perspective view of a heat transfer element 102 in usewithin a blood vessel, showing only one helical lobe per segment forpurposes of clarity. Beginning from the proximal end of the heattransfer element (not shown in FIG. 15), as the blood moves forward, thefirst helical heat transfer segment 134 induces a counter-clockwiserotational inertia to the blood. As the blood reaches the second segment104, the rotational direction of the inertia is reversed, causing mixingwithin the blood. Further, as the blood reaches the third segment 106,the rotational direction of the inertia is again reversed. The suddenchanges in flow direction actively reorient and randomize the velocityvectors, thus ensuring mixing throughout the bloodstream. During suchmixing, the velocity vectors of the blood become more random and, insome cases, become perpendicular to the axis of the vessel. Thus, alarge portion of the volume of warm blood in the vessel is activelybrought in contact with the heat transfer element 102 where it can becooled by direct contact rather than being cooled largely by conductionthrough adjacent laminar layers of blood.

Referring back to FIG. 12, the heat transfer element 102 has beendesigned to address all of the design criteria discussed above. First,the heat transfer element 102 is flexible and is made of a highlyconductive material. The flexibility is provided by a segmentaldistribution of bellows sections 140, 108 that provide an articulatingmechanism. Bellows have a known convoluted design that provideflexibility. Second, the exterior surface area 152 has been increasedthrough the use of helical ridges 138, 144, 148 and helical grooves 136,142, 146. The ridges also allow the heat transfer element 102 tomaintain a relatively atraumatic profile, thereby minimizing thepossibility of damage to the vessel wall. Third, the heat transferelement 102 has been designed to promote mixing both internally andexternally. The modular or segmental design allows the direction of thegrooves to be reversed between segments. The alternating helicalrotations create an alternating flow that results in mixing the blood ina manner analogous to the mixing action created by the rotor of awashing machine that switches directions back and forth. This action isintended to promote mixing to enhance the heat transfer rate. Thealternating helical design also causes beneficial mixing, or turbulentkinetic energy, of the working fluid flowing internally.

FIG. 16 is a perspective view of a third embodiment of a heat transferelement 160 according to the present invention. The heat transferelement 160 is comprised of a series of elongated, articulated segmentsor modules 162. A first elongated heat transfer segment 162 is locatedat the proximal end of the heat transfer element 160. The segment 162may be a smooth right circular cylinder, as addressed in FIG. 9, or itcan incorporate a turbulence-inducing or mixing-inducing exteriorsurface. The turbulence-inducing or mixing-inducing exterior surfaceshown on the segment 162 in FIG. 16 comprises a plurality of parallellongitudinal ridges 164 with parallel longitudinal grooves 168therebetween. One, two, three, or more parallel longitudinal ridges 164could be used without departing from the spirit of the presentinvention. In the embodiment where they are used, the longitudinalridges 164 and the longitudinal grooves 168 of the heat transfer segment162 are aligned parallel with the axis of the first heat transfersegment 162.

The first heat transfer segment 162 is coupled to a second elongatedheat transfer segment 162 by a first flexible section such as a bellowssection 166, which provides flexibility and compressibility.Alternatively, the flexible section may be a simple flexible tube, verysimilar to a smooth heat transfer segment as addressed in FIG. 9, butflexible. The second heat transfer segment 162 also comprises aplurality of parallel longitudinal ridges 164 with parallel longitudinalgrooves 168 therebetween. The longitudinal ridges 164 and thelongitudinal grooves 168 of the second heat transfer segment 162 arealigned parallel with the axis of the second heat transfer segment 162.The second heat transfer segment 162 is coupled to a third elongatedheat transfer segment 162 by a second flexible section such as a bellowssection 166 or a flexible tube. The third heat transfer segment 162 alsocomprises a plurality of parallel longitudinal ridges 164 with parallellongitudinal grooves 168 therebetween. The longitudinal ridges 164 andthe longitudinal grooves 168 of the third heat transfer segment 162 arealigned parallel with the axis of the third heat transfer segment 162.Further, in this embodiment, adjacent heat transfer segments 162 of theheat transfer element 160 have their longitudinal ridges 164 alignedwith each other, and their longitudinal grooves 168 aligned with eachother.

In addition, the rounded contours of the ridges 164 also allow the heattransfer element 160 to maintain a relatively atraumatic profile,thereby minimizing the possibility of damage to the blood vessel wall. Aheat transfer element 160 according to the present invention may becomprised of two, three, or more heat transfer segments 162.

The bellows sections 166 are formed from seamless and nonporousmaterials, such as metal, and therefore are impermeable to gas, whichcan be particularly important, depending on the type of working fluidwhich is cycled through the heat transfer element 160. The structure ofthe bellows sections 166 allows them to bend, extend and compress, whichincreases the flexibility of the heat transfer element 160 so that it ismore readily able to navigate through blood vessels. The bellowssections 166 also provide for axial compression of the heat transferelement 160, which can limit the trauma when the distal end of the heattransfer element 160 abuts a blood vessel wall. The bellows sections 166are also able to tolerate cryogenic temperatures without a loss ofperformance.

FIG. 17 is a perspective view of a fourth embodiment of a heat transferelement 170 according to the present invention. The heat transferelement 170 is comprised of a series of elongated, articulated segmentsor modules 172. A first elongated heat transfer segment 172 is locatedat the proximal end of the heat transfer element 170. Aturbulence-inducing or mixing-inducing exterior surface of the segment172 comprises a plurality of parallel longitudinal ridges 174 withparallel longitudinal grooves 176 therebetween. One, two, three, or moreparallel longitudinal ridges 174 could be used without departing fromthe spirit of the present invention. In this embodiment, thelongitudinal ridges 174 and the longitudinal grooves 176 of the heattransfer segment 172 are aligned parallel with the axis of the firstheat transfer segment 172.

The first heat transfer segment 172 is coupled to a second elongatedheat transfer segment 172 by a first flexible section such as a bellowssection 178, which provides flexibility and compressibility.Alternatively, the flexible section may be a simple flexible tube, verysimilar to a smooth heat transfer segment as shown in FIG. 9, butflexible. The second heat transfer segment 172 also comprises aplurality of parallel longitudinal ridges 174 with parallel longitudinalgrooves 176 therebetween. The longitudinal ridges 174 and thelongitudinal grooves 176 of the second heat transfer segment 172 arealigned parallel with the axis of the second heat transfer segment 172.The second heat transfer segment 172 is coupled to a third elongatedheat transfer segment 172 by a second flexible section such as a bellowssection 178 or a flexible tube. The third heat transfer segment 172 alsocomprises a plurality of parallel longitudinal ridges 174 with parallellongitudinal grooves 176 therebetween. The longitudinal ridges 174 andthe longitudinal grooves 176 of the third heat transfer segment 172 arealigned parallel with the axis of the third heat transfer segment 172.Further, in this embodiment, adjacent heat transfer segments 172 of theheat transfer element 170 have their longitudinal ridges 174 angularlyoffset from each other, and their longitudinal grooves 176 angularlyoffset from each other. Offsetting of the longitudinal ridges 174 andthe longitudinal grooves 176 from each other on adjacent segments 172promotes turbulence or mixing in blood flowing past the exterior of theheat transfer element 170.

FIG. 18 is a transverse section view of a heat transfer segment 180,illustrative of segments 162, 172 of heat transfer elements 160, 170shown in FIG. 16 and FIG. 17. The coaxial construction of the heattransfer segment 180 is clearly shown. The inner coaxial lumen 182 isdefined by the insulating coaxial tube 184. The outer lumen 190 isdefined by the exterior surface of the insulating coaxial tube 184 andthe interior surface 192 of the heat transfer segment 180. In addition,parallel longitudinal ridges 186 and parallel longitudinal grooves 188may be seen in FIG. 18. The longitudinal ridges 186 and the longitudinalgrooves 188 may have a relatively rectangular cross-section, as shown inFIG. 18, or they may be more triangular in cross-section, as shown inFIGS. 16 and 17. The longitudinal ridges 186 and the longitudinalgrooves 188 may be formed only on the exterior surface of the segment180, with a cylindrical interior surface 192. Alternatively,corresponding longitudinal ridges and grooves may be formed on theinterior surface 192 as shown, to promote turbulence or mixing in theworking fluid. Although FIG. 18 shows six ridges and six grooves, thenumber of ridges and grooves may vary. Where a smooth exterior surfaceis desired, the outer tube of the heat transfer segment 180 could havesmooth outer and inner surfaces, like the inner tube 184. Alternatively,the outer tube of the heat transfer segment 180 could have a smoothouter surface and a ridged inner surface like the interior surface 192shown in FIG. 18.

FIG. 19 is a cut-away perspective view of an alternative embodiment of aheat transfer element 194. An external surface 196 of the heat transferelement 194 is covered with a series of axially staggered protrusions198. The staggered nature of the outer protrusions 198 is readily seenwith reference to FIG. 20 which is a transverse cross-sectional viewtaken at a location denoted by the line 6-6 in FIG. 19. As the bloodflows along the external surface 196, it collides with one of thestaggered protrusions 198 and a turbulent wake flow is created behindthe protrusion. As the blood divides and swirls alongside of the firststaggered protrusion 198, its turbulent wake encounters anotherstaggered protrusion 198 within its path preventing the re-lamination ofthe flow and creating yet more mixing. In this way, the velocity vectorsare randomized and mixing is created not only in the boundary layer butalso throughout a large portion of the free stream. As is the case withthe preferred embodiment, this geometry also induces a mixing effect onthe internal working fluid flow. A working fluid is circulated upthrough an inner lumen 200 defined by an insulating tube 202 to a distaltip of the heat transfer element 194. The working fluid then traversesan outer lumen 204 in order to transfer heat to the exterior surface 196of the heat transfer element 194. The inside surface of the heattransfer element 194 is similar to the exterior surface 196 in order toinduce turbulent flow of the working fluid. The inner protrusions can bealigned with the outer protrusions 198 as shown in FIG. 20 or they canbe offset from the outer protrusions 198 as shown in FIG. 19.

With reference to FIGS. 21 and 22, a catheter 206 constructed inaccordance with an alternative embodiment of the invention will now bedescribed. The catheter 206 includes an elongated catheter body 208 witha heat transfer element 210 located at a distal portion 212 of thecatheter body 208. The catheter 206 includes a multiple lumenarrangement 214 to deliver fluid to and from an interior 216 of the heattransfer element 210 and allow the catheter 206 to be placed into ablood vessel over a guidewire. The heat transfer element 210 includesturbulence-inducing invaginations 218 located on an exterior surface252. Similar invaginations may be located on an interior surface 220 ofthe heat transfer element 210, but are not shown for clarity. Further,it should be noted that the heat transfer element 210 is shown with onlyfour invaginations 218. Other embodiments may employ multiple elementsconnected by flexible joints or bellows as disclosed above. A singleheat transfer element is shown in FIG. 21 merely for clarity. In analternative embodiment of the invention, any of the other heat-transferelements described herein may replace heat transfer element 212.Alternatively, the multi-lumen arrangement may be used to deliver fluidto and from the interior of an operative element(s) other than aheat-transfer-element such as, but without limitation, a catheterballoon, e.g., a dilatation balloon.

The catheter 206 includes an integrated elongated multiple lumen membersuch as a bitumen member 222 having a first lumen member 226 and asecond lumen member 228. The bitumen member 222 has a substantiallyfigure-eight cross-sectional shape (FIG. 22) and an outer surface 224with the same general shape. The first lumen member 226 includes aninterior surface 230 defining a first lumen or guide wire lumen 232having a substantially circular cross-sectional shape. The interiorsurface 230 may be coated with a lubricious material to facilitate thesliding of the catheter 206 over a guidewire. The first lumen member 226further includes a first exterior surface 242 and a second exteriorsurface 244. The first lumen 232 is adapted to receive a guide wire forplacing the catheter 206 into a blood vessel over the guidewire in awell-known manner.

In FIGS. 21 and 22, the guide wire lumen 232 is not coaxial with thecatheter body 208. In an alternative embodiment of the invention, theguide wire lumen 232 may be coaxial with the catheter body 208.

The second lumen member 228 includes a first interior surface 246 and asecond interior surface 248, which is the same as the second exteriorsurface 244 of the first lumen member 226, that together define a secondlumen or supply lumen 250 having a substantially luniformcross-sectional shape. The second lumen member 228 further includes anexterior surface 252. The second lumen 250 has a cross-sectional areaA₂. The second lumen 250 is adapted to supply working fluid to theinterior of the heat transfer element 210 to provide temperature controlof a flow or volume of blood in the manner described above.

The second lumen member 228 terminates short of a distal end 236 of thecatheter 206, leaving sufficient space for the working fluid to exit thesupply lumen 250 so it can contact the interior surface 220 of the heattransfer element 210 for heat transfer purposes.

Although the second lumen member 228 is shown as a single supply lumenterminating adjacent the distal end 236 of catheter 206 to deliverworking fluid at the distal end of the catheter 206, with reference toFIG. 23, in an alternative embodiment of the invention, a single supplylumen member 254 may include one or more outlet openings 256 adjacentthe distal end 236 of the catheter 206 and one or more outlet openings258 adjacent a mid-point along the interior length of the heat transferelement 210. This arrangement improves the heat transfer characteristicsof the heat-transfer element 210 because fresh working fluid at the sametemperature is delivered separately to each segment 104, 106 of theinterior of the heat-transfer element 210 instead of in series.

Although two heat transfer segments 104, 106 are shown, it will bereadily apparent that a number of heat transfer segments other than two,e.g., one, three, four, etc., may be used.

It will be readily apparent to those skilled in the art that in anotherembodiment of the invention, in addition to the one or more openings 256in the distal portion of the heat transfer element 210, one or moreopenings at one or more locations may be located anywhere along theinterior length of the heat transfer element 210 proximal to the distalportion.

With reference to FIG. 24, in an alternative embodiment of theinvention, first and second supply lumen members 260, 262 definerespective first and second supply lumens 264, 266 for supplying workingfluid to the interior of the heat transfer element 210. The first supplylumen 260 terminates just short of the distal end 236 of the catheter206 to deliver working fluid at the distal portion of the heat transferelement 210. The second supply lumen 262 terminates short of the distalportion of the catheter 206, for example, at approximately a mid-lengthpoint along the interior of the heat transfer element 210 for deliveringworking fluid to the second heat transfer segment 104. In an alternativeembodiment of the invention, the second lumen member 262 may terminateanywhere along the interior length of the heat transfer element 210proximal to the distal portion of the heat transfer element 210.Further, a number of supply lumens 262 greater than two may terminatealong the interior length of the heat transfer element 210 fordelivering a working fluid at a variety of points along the interiorlength of the heat transfer element 210.

With reference back to FIGS. 21 and 22, the bitumen member 222 ispreferably extruded from a material such as polyurethane or Pebax. In anembodiment of the invention, the bitumen member is extrudedsimultaneously with the catheter body 208. In an alternative embodimentof the invention, the first lumen member 226 and second lumen member 228are formed separately and welded or fixed together.

A third lumen or return lumen 238 provides a convenient return path forworking fluid. The third lumen 238 is substantially defined by theinterior surface 220 of the heat transfer element 210, an interiorsurface 240 of the catheter body 208, and the exterior surface 224 ofthe bitumen member 222. The inventors have determined that the workingfluid pressure drop through the lumens is minimized when the third lumen238 has a hydraulic diameter D₃ that is equal to 0.75 of the hydraulicdiameter D)₂ of the second lumen 250. However, the pressure drop thatoccurs when the ratio of the hydraulic diameter D₃ to the hydraulicdiameter D₂ is substantially equal to 0.75, i.e., 0.75±0.10, works well.For flow through a cylinder, the hydraulic diameter D of a lumen isequal to four times the cross-sectional area of the lumen divided by thewetted perimeter. The wetted perimeter is the total perimeter of theregion defined by the intersection of the fluid path through the lumenand a plane perpendicular to the longitudinal axis of the lumen. Thewetted perimeter for the return lumen 238 would include an inner wettedperimeter (due to the outer surface 224 of the bitumen member 222) andan outer wetted perimeter (due to the interior surface 240 of thecatheter body 208). The wetted perimeter for the supply lumen 250 wouldinclude only an outer wetted perimeter (due to the first and secondinterior surfaces 246, 248 of the bitumen member 222). Thus, the wettedperimeter for a lumen depends on the number of boundary surfaces thatdefine the lumen.

The third lumen 238 is adapted to return working fluid delivered to theinterior of the heat transfer element 210 back to an external reservoiror the fluid supply for recirculation in a well-known manner.

In an alternative embodiment the third lumen 238 is the supply lumen andthe second lumen 250 is the return lumen. Accordingly, it will bereadily understood by the reader that adjectives such as “first,”“second,” etc. are used to facilitate the reader's understanding of theinvention and are not intended to limit the scope of the invention,especially as defined in the claims.

In a further embodiment of the invention, the member 222 may include anumber of lumens other than two such as, for example, 1, 3, 4, 5, etc.Additional lumens may be used as additional supply and/or return lumens,for other instruments, e.g., imaging devices, or for other purposes,e.g., inflating a catheter balloon or delivering a drug.

Heating or cooling efficiency of the heat transfer element 210 isoptimized by maximizing the flow rate of working fluid through thelumens 250, 238 and minimizing the transfer of heat between the workingfluid and the supply lumen member. Working fluid flow rate is maximizedand pressure drop minimized in the present invention by having the ratioof the hydraulic diameter D₃ of the return lumen 238 to the hydraulicdiameter D₂ of the supply lumen 250 equal to 0.75. However, a ratiosubstantially equal to 0.75, i.e., 0.75±10-20%, is acceptable. Heattransfer losses are minimized in the supply lumen 250 by minimizing thesurface area contact made between the bitumen member 222 and the workingfluid as it travels through the supply lumen member. The surface area ofthe supply lumen member that the supplied working fluid contacts is muchless than that in co-axial or concentric lumens used in the past becausethe supplied working fluid only contacts the interior of one lumenmember compared to contacting the exterior of one lumen member and theinterior of another lumen member. Thus, heat transfer losses areminimized in the embodiments of the supply lumen in the multiple lumenmember 222 of the present invention.

It will be readily apparent to those skilled in the art that the supplylumen 250 and the return lumen 238 may have cross-sectional shapes otherthan those shown and described herein and still maintain the desiredhydraulic diameter ratio of substantially 0.75. With reference to FIGS.25 and 26, an example of a catheter 206 including a supply lumen and areturn lumen constructed in accordance with an alternative preferredembodiment of the invention, where the hydraulic diameter ratio of thereturn lumen to the supply lumen is substantially equal to 0.75 isillustrated. It should be noted, the same elements as those describedabove with respect to FIGS. 21 and 22 are identified with the samereference numerals and similar elements are identified with the samereference numerals, but with a (′) suffix.

The catheter 206 illustrated in FIGS. 25 and 26 includes a multiplelumen arrangement 214′ for delivering working fluid to and from aninterior 216 of the heat transfer element 210 and allowing the catheterto be placed into a blood vessel over a guide wire. The multiple lumenarrangement 214′ includes a bitumen member 222′ with a slightlydifferent construction from the bi-lumen member 222 discussed above withrespect to FIGS. 21 and 22. Instead of an outer surface 224 that isgenerally figure-eight shaped, the bitumen member 222′ has an outersurface 224′ that is circular. Consequently, the third lumen 238′ has anannular cross-sectional shape.

As discussed above, maintaining the hydraulic diameter ratio of thereturn lumen 250′ to the supply lumen 238′ substantially equal to 0.75maximizes the working fluid flow rate through the multiple lumenarrangement 214′.

In addition, the annular return lumen 238′ enhances the convective heattransfer coefficient within the heat transfer element 210, especiallyadjacent an intermediate segment or bellows segment 268. Working fluidflowing through the annular return lumen 238′, between the outer surface224′ of the bitumen member 222′ and the inner surface 220 of the heattransfer element, encounters a restriction 270 caused by the impingementof the bellows section 268 into the flow path. Although the impingementof the bellows section 268 is shown as causing the restriction 270 inthe flow path of the return lumen 238′, in an alternative embodiment ofthe invention, the bitumen member 222′ may create the restriction 270 bybeing thicker in this longitudinal region of the bi-lumen member 222′.The distance between the bitumen member 222′ and the bellows section 268is such that the characteristic flow resulting from a flow of workingfluid is at least of a transitional nature.

For a specific working fluid flux or flow rate (cc/sec), the mean fluidvelocity through the bellows section restriction 270 will be greaterthan the mean fluid velocity obtained through the annular return lumen238′ in the heat transfer segment 104, 106 of the heat transfer element210. Sufficiently high velocity through the bellows section restriction270 will result in wall jets 272 directed into the interior portion 220of the heat transfer segment 104. The wall jets 272 enhance the heattransfer coefficient within the helical heat transfer segment 104because they enhance the mixing of the working fluid along the interiorof the helical heat transfer segment 104. Increasing the velocity of thejets 272 by increasing the working fluid flow rate or decreasing thesize of the restriction 270 will result in a transition closer to thejet exit and greater mean turbulence intensity throughout the helicalheat transfer segment 104. Thus, the outer surface 224′ of the bi-lumenmember 222′, adjacent the bellows 268, and the inner surface of thebellows 268 form means for further enhancing the transfer of heatbetween the heat transfer element 210 and the working fluid, in additionto that caused by the interior portion 220 of the helical heat transfersegment 104.

In an alternative embodiment of the invention, as described above, theheat transfer element may include a number of heat transfer segmentsother than two, i.e., 1, 3, 4, etc., with a corresponding number ofintermediate segments, i.e., the number of heat transfer segments minusone.

The embodiment of the multiple lumen arrangement 222 discussed withrespect to FIGS. 21 and 22 would not enhance the convective heattransfer coefficient as much as the embodiment of the multiple lumenarrangement 222′ discussed with respect to FIGS. 25 and 26 becauseworking fluid would preferentially flow through the larger areas of thereturn lumen 238, adjacent the junction of the first lumen member 226and second lumen member 228. Thus, high-speed working fluid would havemore contact with the outer surface 224 of the bitumen member 222 andless contact with the interior portion of 220 heat transfer element 210.In contrast, the annular return lumen 238′ of the multiple lumenarrangement 222′ causes working fluid flow to be axisymmetric so thatsignificant working fluid flow contacts all areas of the helical segmentequally.

On the other hand, the heat transfer element according to an embodimentof the present invention may also be made of a flexible material, suchas latex rubber. The latex rubber provides a high degree of flexibilitywhich was previously achieved by articulation. The latex rubber furtherallows the heat transfer element to be made collapsible so that whendeflated the same may be easily inserted into an artery. Insertion andlocation may be conveniently made by way of a guide catheter or guidewire. Following insertion and location in the desired artery, the heattransfer element may be inflated for use by a working fluid such assaline, water, perfluorocarbons, or other suitable fluids.

A heat transfer element made of a flexible material generally hassignificantly less thermal conductivity than a heat transfer elementmade of metal. The device compensates for this by enhancing the surfacearea available for heat transfer. This may be accomplished in two ways:by increasing the cross-sectional size and by increasing the length.Regarding the former, the device may be structured to be large wheninflated, because when deflated the same may still be inserted into anartery. In fact, the device may be as large as the arterial wall, solong as a path for blood flow is allowed, because the flexibility of thedevice tends to prevent damage to the arterial wall even upon contact.Such paths are described below. Regarding the latter, the device may beconfigured to be long. One way to configure a long device is to taperthe same so that the device may fit into distal arteries having reducedradii in a manner described below. The device further compensates forthe reduced thermal conductivity by reducing the thickness of the heattransfer element wall.

Embodiments of the device use a heat transfer element design thatproduces a high level of turbulence in the free stream of the blood andin the working fluid. One embodiment of the invention forces a helicalmotion on the working fluid and imposes a helical barrier in the blood,causing turbulence. In an alternative embodiment the helical barrier istapered. In a second alternative embodiment, a tapered inflatable heattransfer element has surface features to cause turbulence. As oneexample, the surface features may have a spiral shape. In anotherexample, the surface features may be staggered protrusions. In all ofthese embodiments, the design forces a high level of turbulence in thefree stream of the blood by causing the blood to navigate a tortuouspath while passing through the artery. This tortuous path causes theblood to undergo violent accelerations resulting in turbulence.

In a third alternative embodiment of the invention, a taper of aninflatable heat transfer element provides enough additional surface areaper se to cause sufficient heat transfer. In all of the embodiments, theinflation is performed by the working fluid, such as water or saline.

Referring to FIG. 27, a side view is shown of a first embodiment of aheat transfer element 272 according to an embodiment of the invention.The heat transfer element 272 is formed by an inlet lumen 276 and anoutlet lumen 274. In this embodiment, the outlet lumen 274 is formed ina helix shape surrounding the inlet lumen 276 that is formed in a pipeshape. The names of the lumens are of course not limiting. It will beclear to one skilled in the art that the inlet lumen 276 may serve as anoutlet and the outlet lumen 274 may serve as an inlet. It will also beclear that the heat transfer element is capable of both heating (bydelivering heat to) and cooling (by removing heat from) a desired area.

The heat transfer element 272 is rigid but flexible so as to beinsertable in an appropriate vessel by use of a guide catheter.Alternatively, the heat transfer element may employ a device forthreading a guide wire therethrough to assist placement within anartery. The heat transfer element 272 has an inflated length of L, ahelical diameter of D_(c), a tubal diameter of d, and a helical angle ofα. For example, D_(c) may be about 3.3 mm and d may be about 0.9 mm to 1mm. Of course, the tubal diameter d need not be constant. For example,the diameter of the inlet lumen 276 may differ from that of the outletlumen 272.

The shape of the outlet lumen 274 in FIG. 27 is helical. This helicalshape presents a cylindrical obstacle, in cross-section, to the flow ofblood. Such obstacles tend to create turbulence in the free stream ofblood. In particular, the form of turbulence is the creation of vonKarman vortices in the wake of the flow of blood, downstream of thecylindrical obstacles.

Typical inflatable materials are not highly thermally conductive. Theyare much less conductive than the metallic heat transfer elementdisclosed in the patent application incorporated by reference above. Thedifference in conductivity is compensated for in at least two ways inthe present device. The material is made thinner and the heat transferelement is afforded a larger surface area. Regarding the former, thethickness may be less than about ½ mil for adequate cooling.

Thin inflatable materials, particularly those with large surface areas,may require a structure, such as a wire, within their interiors tomaintain their approximate uninflated positions so that upon inflation,the proper form is achieved. Thus, a wire structure 282 is shown in FIG.27 which may be advantageously disposed within the inflatable materialto perform such a function.

Another consideration is the angle α of the helix. Angle α should bedetermined to optimize the helical motion of the blood around the lumens274 and 276, enhancing heat transfer. Of course, angle α should also bedetermined to optimize the helical motion of the working fluid withinthe lumens 274 and 276. The helical motion of the working fluid withinthe lumens 274 and 276 increases the turbulence in the working fluid bycreating secondary motions. In particular, helical motion of a fluid ina pipe induces two counter-rotating secondary flows.

An enhancement of h_(c) would be obtained in this system, and thisenhancement may be described by a Nusselt number Nu of up to about 10 oreven more.

The above discussion describes one embodiment of a heat transferelement. An alternative embodiment of the device, shown in a side viewin FIG. 28, illustrates a heat transfer element 286 with a surface areaenhancement. Increasing the surface area of the inflatable materialenhances heat transfer. The heat transfer element 272 includes a seriesof coils or helices of different coil diameters and tubal diameters. Itis not strictly necessary that the tubal diameters differ, but it islikely that commercially realizable systems will have differing tubaldiameters. The heat transfer element 272 may taper either continuouslyor segnentally.

This alternative embodiment enhances surface area in two ways. First,the use of smaller diameter lumens enhances the overallsurface-to-volume ratio. Second, the use of progressively smaller (i.e.,tapered) lumens allows a distal end 312 to be inserted further into anartery than would be possible with the embodiment of FIG. 27.

In the embodiment of FIG. 28, a first coil segment 288 is shown havinglength L₁ and diameter D_(C1). The first coil segment 288 is formed ofan inlet lumen 296 having diameter d₁ and an outlet lumen 298 havingdiameter d₁′. In the first coil segment, as well as the others, theoutlet lumen need not immediately drain the inlet lumen. In FIG. 28, theinlet lumen for each segment feeds the inlet lumen of the succeedingsegment except for an inlet lumen adjacent a distal end 312 of the heattransfer element 286 which directly feeds its corresponding outletlumen.

A separate embodiment may also be constructed in which the inlet lumenseach provide working fluid to their corresponding outlet lumens. In thisembodiment, either a separate lumen needs to be provided to drain eachoutlet lumen or each outlet lumen drains into the adjacent outlet lumen.This embodiment has the advantage that an opposite helicity may beaccorded each successive segment. The opposite helicities in turnenhance the turbulence of the working fluid flowing past them.

A second coil segment 290 is shown having length L₂ and diameter D_(C2).The second coil segment 290 is formed of an inlet lumen 300 havingdiameter d₂ and an outlet lumen 302 having diameter d₂′. A third coilsegment 292 is shown having length L₃ and diameter D_(C3). The thirdcoil segment 292 is formed of an inlet lumen 304 having diameter d₃ andan outlet lumen 306 having diameter d₃′. Likewise, a fourth coil segment294 is shown having length L₄ and diameter D_(C4). The fourth coilsegment 294 is formed of an inlet lumen 308 having diameter d₄ and anoutlet lumen 310 having diameter d₄′. The diameters of the lumens,especially that of the lumen located at or near distal end 312, shouldbe large enough to not restrict the flow of the working fluid withinthem. Of course, any number of lumens may be provided depending on therequirements of the user.

FIG. 29 shows the connection between two adjacent inlet lumens 296 and300. A joint 314 is shown coupling the two lumens. The construction ofthe joint may be by way of variations in stress, hardening, etc.

An advantage to this alternative embodiment arises from the smallerdiameters of the distal segments. The heat transfer element of FIG. 28may be placed in smaller workspaces than the heat transfer element ofFIG. 27. For example, a treatment for brain trauma may include placementof a cooling device in the internal carotid artery of a patient. Asnoted above, the common carotid artery feeds the internal carotidartery. In some patients, the heat transfer element of FIG. 27 may notfit in the internal carotid artery. Similarly, the first coil segment ofthe heat transfer element in FIG. 28 may not easily fit in the internalcarotid artery, although the second, third, and fourth segments may fit.Thus, in the embodiment of FIG. 28, the first coil segment may remain inthe common carotid artery while the segments of smaller diameter (thesecond, third, and fourth) may be placed in the internal carotid artery.In fact, in this embodiment, D_(C1) may be large, such as 5-6 mm. Theoverall length of the heat transfer element 286 may be, e.g., about 20to 25 cm. Of course, such considerations play less of a role when thedevice is placed in a large vein such as the inferior vena cava.

An additional advantage was mentioned above. The surface area of thealternative embodiment of FIG. 28 may be substantially larger than thatof the embodiment of FIG. 27, resulting in significantly enhanced heattransfer. For example, the enhancement in surface area may besubstantial, such as up to or even more than three times compared to thesurface area of the device of the application incorporated by referenceabove. An additional advantage of both embodiments is that the helicalrounded shape allows atraumatic insertion into cylindrical cavities suchas, e.g., arteries.

The embodiment of FIG. 28 may result in an Nu from 1 up to about 50.

FIG. 30 shows a second alternative embodiment of the device employingsurface features rather than overall shape to induce turbulence. Inparticular, FIG. 30 shows a heat transfer element 314 having an inletlumen (not shown) and an outlet inflatable lumen 328 having foursegments 316, 318, 320, and 330. Segment 346 is adjacent a proximal end326 and segment 330 is adjacent a distal end 322. The segments arearranged having reducing radii in the direction of the proximal end tothe distal end. In a manner similar to that of the embodiment of FIG.28, the feature of reducing radii allows insertion of the heat transferelement into small work places such as small arteries.

Heat transfer element 314 has a number of surface features 324 disposedthereon. The surface features 324 may be constructed with, e.g., varioushardening treatments applied to the heat transfer element 314, oralternatively by injection molding. The hardening treatments may resultin a wavy or corrugated surface to the exterior of heat transfer element314. The hardening treatments may further result in a wavy or corrugatedsurface to the interior of heat transfer element 314. FIG. 31 shows avariation of this embodiment, in which a fabrication process is usedwhich results in a spiral or helical shape to the surface features.

The embodiment of FIG. 30 may result in an Nu of about 1 to 50.

In another variation of this embodiment, shown in FIG. 33, a heattransfer element 356 employs a plurality of protrusions 360 on outletlumen 358 which surrounds an inlet lumen 364. In particular, FIG. 33 isa cut-away perspective view of an alternative embodiment of a heattransfer element 356. A working fluid is circulated through an inletlumen 362 to a distal tip of the heat transfer element 356 therebyinflating the heat transfer element 356. The working fluid thentraverses an outlet coaxial lumen 366 in order to transfer heat from theexterior surface 358 of the heat transfer element 356. The insidestructure of the heat transfer element 356 is similar to the exteriorstructure in order to induce turbulent flow of the working fluid.

An external surface 358 of the inflatable heat transfer element 356 iscovered with a series of staggered protrusions 360. The staggered natureof the protrusions 360 is readily seen with reference to FIG. 34 whichis a transverse cross-sectional view of an inflated heat transferelement taken along the line 8-8 in FIG. 33. In order to induce freestream turbulence, the height, d_(p), of the staggered protrusions 360is greater than the thickness of the boundary layer which would developif a smooth heat transfer element had been introduced into the bloodstream. As the blood flows along the external surface 358, it collideswith one of the staggered protrusions 360 and a turbulent flow iscreated. As the blood divides and swirls along side of the firststaggered protrusion 360, it collides with another staggered protrusion360 within its path preventing the re-lamination of the flow andcreating yet more turbulence. In this way, the velocity vectors arerandomized and free stream turbulence is created. As is the case withthe other embodiments, this geometry also induces a turbulent effect onthe internal coolant flow.

The embodiment of FIG. 33 may result in an Nu of about 1 to 50.

Of course, other surface features may also be used which result inturbulence in fluids flowing past them. These include spirals, helices,protrusions, various polygonal bodies, pyramids, tetrahedrons, wedges,etc.

In some situations, an enhanced surface area alone, without the creationof additional turbulence, may result in sufficient heat transfer to coolthe blood. Referring to FIG. 32, a heat transfer element 332 is shownhaving an inlet lumen 334 and an outlet lumen 336. The inlet lumen 334provides a working fluid to the heat transfer element 332 and outletlumen 336 drains the working fluid from the same. The functions may, ofcourse, be reversed. The heat transfer element 332 is further dividedinto five segments, although more or less may be provided as dictated byrequirements of the user. The five segments in FIG. 32 are denotedsegments 338, 340, 342, 344, and 346. In FIG. 32, the segment 338 has afirst and largest radius R₁, followed by corresponding radii forsegments 340, 342, 344, and 346. Segment 346 has a second and smallestradius. The length of the segment 338 is L₁, followed by correspondinglengths for segments 340, 342, 344, and 346.

A purely tapered (nonsegmented) form may replace the tapered segmentalform, but the former may be more difficult to manufacture. In eithercase, the tapered form allows the heat transfer element 332 to bedisposed in small arteries, i.e., arteries with radii smaller than R₁. Asufficient surface area is thus afforded even in very small arteries toprovide the required heat transfer.

The surface area and thus the size of the device should be substantialto provide the necessary heat transfer. Example dimensions for athree-segmented tapered form may be as follows: L₁=10 cm, R₁=2.5 mm;L₂=10 cm, R₂=1.65 mm, L₃=5 cm, R₃=1 mm. Such a heat transfer elementwould have an overall length of 25 cm and a surface area of 3×10⁻⁴ m².

The embodiment of FIG. 32 results in an enhancement of the heat transferrate of up to about 300% due to the increased surface area S alone.

A variation of the embodiment of FIG. 32 includes placing at least oneturbulence-inducing surface feature within the interior of the outletlumen 336. This surface feature may induce turbulence in the workingfluid, thereby increasing the convective heat transfer rate in themanner described above.

Another variation of the embodiment of FIG. 32 involves reducing thejoint diameter between segments (not shown). For example, the inflatablematerial may be formed such that joints 348, 350, 352, and 354 have adiameter only slightly greater than that of the inlet lumen 334. Inother words, the heat transfer element 332 has a tapered “sausage”shape.

In all of the embodiments, the inflatable material may be formed fromseamless and nonporous materials which are therefore impermeable to gas.Impermeability can be particularly important depending on the type ofworking fluid which is cycled through the heat transfer element. Forexample, the inflatable material may be latex or other such rubbermaterials, or alternatively of any other material with similarproperties under inflation. The flexible material allows the heattransfer element to bend, extend and compress so that it is more readilyable to navigate through tiny blood vessels. The material also providesfor axial compression of the heat transfer element which can limit thetrauma when the distal end of the heat transfer element 272 abuts ablood vessel wall. The material should be chosen to toleratetemperatures in the range of −1° C. to 37° C., or even higher in thecase of blood heating, without a loss of performance.

It may be desirable to treat the surface of the heat transfer element toavoid clot formation because the heat transfer element may dwell withinthe blood vessel for extended periods of time, such as 24-48 hours oreven longer. One means by which to prevent thrombus formation is to bindan antithrombogenic agent to the surface of the heat transfer element.For example, heparin is known to inhibit clot formation and is alsoknown to be useful as a biocoating.

Referring back to FIG. 27, an embodiment of the method of the inventionwill be described. A description with reference to the other embodimentsis analogous. A guide catheter or wire may be disposed up to or near thearea to be cooled or heated. The case of a guide catheter will bediscussed here. The heat transfer element may be fed through the guidecatheter to the area. Alternatively, the heat transfer element may forma portion of the guide catheter. A portion of the interior of the guidecatheter may form, e.g., the return lumen for the working fluid. In anycase, the movement of the heat transfer element is made significantlymore convenient by the flexibility of the heat transfer element as hasbeen described above.

Once the heat transfer element 272 is in place, a working fluid such assaline or other aqueous solution may be circulated through the heattransfer element 272 to inflate the same. Fluid flows from a supplycatheter into the inlet lumen 276. At the distal end 280 of the heattransfer element 272, the working fluid exits the inlet lumen 276 andenters the outlet lumen 274.

In the case of the embodiment of FIG. 30, for which the description ofFIG. 33 is analogous, the working fluid exits the inlet lumen and entersan outlet inflatable lumen 328 having segments 316, 318, 320, and 330.As the working fluid flows through the outlet lumen 328, heat istransferred from the exterior surface of the heat transfer element 314to the working fluid. The temperature of the external surface may reachvery close to the temperature of the working fluid because the heattransfer element 314 is constructed from very thin material.

The working fluids that may be employed in the device include water,saline or other fluids which remain liquid at the temperatures used.Other coolants, such as freon, undergo nucleated boiling and may createturbulence through a different mechanism. Saline is a safe coolantbecause it is non-toxic and leakage of saline does not result in a gasembolism which may occur with the use of boiling refrigerants.

By enhancing turbulence in the coolant, the coolant can be delivered tothe heat transfer element at a warmer temperature and still achieve thenecessary heat transfer rate. In particular, the enhanced heat transfercharacteristics of the internal structure allow the working fluid to bedelivered to the heat transfer element at lower flow rates and lowerpressures. This is advantageous because high pressures may stiffen theheat transfer element and cause the same to push against the wall of thevessel, thereby shielding part of the heat transfer unit from the blood.Such pressures are unlikely to damage the walls of the vessel because ofthe increased flexibility of the inflated device. The increased heattransfer characteristics allow the pressure of the working fluid to bedelivered at pressures as low as 5 atmospheres, 3 atmospheres, 2atmospheres or even less than 1 atmosphere.

In a preferred embodiment, the heat transfer element creates aturbulence intensity greater than 0.05 in order to create the desiredlevel of turbulence in the entire blood stream during the whole cardiaccycle. The turbulence intensity may be greater than 0.055, 0.06, 0.07 orup to 0.10 or 0.20 or even greater.

As shown in FIG. 35, in another embodiment of the invention the coolingapparatus 368 of the present invention includes a flexible multilumencatheter 370, an inflatable balloon 372, and a plurality of blood flowpassageways 16 through the balloon 372. The balloon 372 is shown in aninflated state, in a selected position in a common carotid artery CC.

The balloon 372 is attached near a distal end of the flexible catheter370. The catheter 370 can have at least a cooling fluid supply lumen 380and a cooling fluid return lumen 382, with the cooling fluid supplylumen 380 preferably being located substantially within the coolingfluid return lumen 382. The catheter 370 can also have a guidewire lumen384, for the passage of a guidewire 386, as is known in the art.

The balloon 372 can be formed from a flexible material, such as apolymer. The balloon 372 can be constructed to assume a substantiallycylindrical shape when inflated, with a proximal aspect 374 and a distalaspect 378. The balloon 372 can have a plurality of tubular shaped bloodflow passageways 376 formed therethrough, from the proximal aspect 374to the distal aspect 378. The tubular walls of the passageways 376constitute a heat transfer surface, for transferring heat from the bloodto the cooling fluid. The flexible material of the tubular passageways376 can be, at least in part, a metallized material, such as a filmcoated with a thin metal layer, either internally, externally, or both,to aid in heat transfer through the passageway walls. Alternatively, thetubular passageways 376 can be constructed of a metal-loaded polymerfilm. Further, the remainder of the balloon 372 can be coated with athin metallized layer, either internally, externally, or both, or ametal-loaded polymer film. The proximal aspect 374 and the distal aspect378 of the balloon can also constitute a heat transfer surface, fortransferring heat from the blood to the cooling fluid. The guidewirelumen 384 of the catheter 370 can also pass through the balloon 372,from the proximal aspect 374 to the distal aspect 378.

As shown in FIG. 36, each tubular passageway 376 has a proximal port 388in a proximal face 390 on the proximal aspect 374 of the balloon 372,and a distal port 392 in a distal face 394 on the distal aspect 378 ofthe balloon 372. A cooling fluid supply port 396 near the distal end ofthe cooling fluid supply lumen 380 supplies chilled saline solution froma chiller (not shown) to the interior of the balloon 372, surroundingthe blood flow passageways 376. A cooling fluid return port 398 in thecooling fluid return lumen 382 returns the saline solution from theinterior of the balloon 372 to the chiller. Relative placement of thecooling fluid ports 396, 398 can be chosen to establish flow counter tothe direction of blood flow, if desired.

FIG. 37 shows the proximal aspect 402 of the balloon 372 and gives aview through the blood flow passageways 376, illustrating the generalarrangement of the blood flow passageways 376, cooling fluid supplylumen 380, cooling fluid return lumen 382, and guidewire lumen 384,within the outer wall 400 of the balloon 372.

FIG. 38 is a side elevation view of the apparatus 368, with a partiallongitudinal section through the balloon wall 400, showing one possiblearrangement of the cooling fluid supply port 396 and the cooling fluidreturn port 398 within the balloon 372.

In practice, the balloon 372, in a deflated state, is passed through thevascular system of a patient on the distal end of the catheter 370, overthe guidewire 386. Placement of the guidewire 386 and the balloon 372can be monitored fluoroscopically, as is known in the art, by use ofradiopaque markers (not shown) on the guidewire 386 and the balloon 372.When the balloon 372 has been positioned at a desired location in thefeeding artery of a selected organ, such as in the common carotid arteryfeeding the brain, fluid such as saline solution is supplied through thecooling fluid supply lumen 380. This fluid passes through the coolingfluid supply port 396 into the interior of the balloon 372, surroundingthe tubular passageways 376, to inflate the balloon 372. Although theballoon 372 can be formed to assume a substantially cylindrical shapeupon unconstrained inflation, the balloon 372 will essentially conformto the shape of the artery within which it is inflated. As the balloon372 inflates, the blood flow passageways 376 open, substantiallyassuming the tubular shape shown.

When the balloon 372 has been properly inflated, blood continues to flowthrough the feeding artery CC by flowing through the blood flowpassageways 376, as indicated, for example, by the arrows in FIG. 35.The size and number of the blood flow passageways 376 are designed toprovide a desired amount of heat transfer surface, while maintaining asuitable amount of blood flow through the feeding artery CC. Return flowto the chiller can be established, to allow flow of cooling fluidthrough the cooling fluid return port 398 and the cooling fluid returnlumen 382 to the chiller. This establishes a continuous flow of coolingfluid through the interior of the balloon 372, around the blood flowpassageways 376. The return flow is regulated to maintain the balloon372 in its inflated state, while circulation of cooling fluid takesplace. The saline solution is cooled in the chiller to maintain adesired cooling fluid temperature in the interior of the balloon 372, toimpart a desired temperature drop to the blood flowing through thetubular passageways 376. This cooled blood flows through the feedingartery to impart the desired amount of cooling to the selected organ.Then, cooling fluid can be evacuated or released from the balloon 372,through the catheter 370, to deflate the balloon 372, and the apparatus368 can be withdrawn from the vascular system of the patient.

Temperature Sensing

A guidewire may also be employed to assist in installing the device. Thetip of the guidewire may contain or be part of a temperature monitor.The temperature monitor may be employed to measure the temperatureupstream or downstream of the heat transfer element and catheter,depending on the direction of blood flow relative to the temperaturemonitor. The temperature monitor may be, e.g., a thermocouple orthermistor.

An embodiment of the invention may employ a thermocouple which ismounted on the end of the guidewire. For the temperatures considered inblood heating or cooling, most of the major thermocouple types may beused, including Types T, E, J, K, G, C, D, R, S, B.

In an alternative embodiment, a thermistor may be used which is attachedto the end of the guidewire. Thermistors are thermally-sensitiveresistors whose resistance changes with a change in body temperature.The use of thermistors may be particularly advantageous for use intemperature-monitoring of blood flow past cooling devices because oftheir sensitivity. For temperature monitoring of body fluids,thermistors that are mostly commonly used include those with a largenegative temperature coefficient of resistance (“NTC”). These shouldideally have a working temperature range inclusive of 25° C. to 40° C.Potential thermistors that may be employed include those with activeelements of polymers or ceramics. Ceramic thermistors may be mostpreferable as these may have the most reproducible temperaturemeasurements. Most thermistors of appropriate sizes are encapsulated inprotective materials such as glass. The size of the thermistor, forconvenient mounting to the guidewire and for convenient insertion in apatient's vasculature, may be about or less than 15 mils. Largerthermistors may be used where desired. Of course, various othertemperature-monitoring devices may also be used as dictated by the size,geometry, and temperature resolution desired.

A signal from the temperature monitoring device may be fed back to thesource of working fluid to control the temperature of the working fluidemerging therefrom. In particular, a catheter may be connected to asource of working fluid. A proximal end of a supply lumen defined by asupply tube is connected at an output port to the source of workingfluid. The return lumen defined by a return tube is similarly connectedat an input port to the source of working fluid. The source of workingfluid can control the temperature of the working fluid emerging from theoutput port. A signal from a circuit may be inputted to the source ofworking fluid at an input. The signal from the circuit may be from thethermocouple, or may alternatively be from any other type oftemperature-monitoring device, such as at the tip of the guidewire.

The signal may advantageously be employed to alter the temperature, ifnecessary, of the working fluid from the source. For example, if thetemperature-monitoring device senses that the temperature of the bloodflowing in the feeding vessel of the patient's vasculature is belowoptimal, a signal may be sent to the source of working fluid to increasethe temperature of the working fluid emerging therefrom. The oppositemay be performed if the temperature-monitoring device senses that thetemperature of the blood flowing in the feeding vessel of the patient'svasculature is above optimal.

Methods of Use Simultaneous Cooling and Heating

FIG. 39 is a schematic representation of an embodiment of the inventionbeing used to cool the body of a patient and to warm a portion of thebody. The hypothermia apparatus shown in FIG. 39 includes a firstworking fluid supply 404, preferably supplying a chilled liquid such aswater, alcohol or a halogenated hydrocarbon, a first supply catheter 406and the cooling element 102. The first supply catheter 406 may have asubstantially coaxial construction. An inner lumen within the firstsupply catheter 406 receives coolant from the first working fluid supply404. The coolant travels the length of the first supply catheter 406 tothe cooling element 102 which serves as the cooling tip of the catheter.At the distal end of the cooling element 102, the coolant exits theinsulated interior lumen and traverses the length of the cooling element102 in order to decrease the temperature of the cooling element 102. Thecoolant then traverses an outer lumen of the first supply catheter 406so that it may be disposed of or recirculated. The first supply catheter406 is a flexible catheter having a diameter sufficiently small to allowits distal end to be inserted percutaneously into an accessible veinsuch as the external jugular vein of a patient as shown in FIG. 39. Thefirst supply catheter 406 is sufficiently long to allow the coolingelement 102 at the distal end of the first supply catheter 406 to bepassed through the vascular system of the patient and placed in thesuperior vena cava 110, inferior vena cava (not shown), or other suchvein.

The method of inserting the catheter into the patient and routing thecooling element 102 into a selected vein is well known in the art.Percutaneous placement of the heat transfer element 102 into the jugularvein is accomplished directly, since the jugular vein is close to thesurface. The catheter would reside in the internal jugular and into thesuperior vena cava or even the right atrium.

Although the working fluid supply 404 is shown as an exemplary coolingdevice, other devices and working fluids may be used. For example, inorder to provide cooling, freon, perfluorocarbon, water, or saline maybe used, as well as other such coolants.

The cooling element can absorb up to or more than 300 Watts of heat fromthe blood stream, resulting in absorption of as much as 100 Watts, 150Watts, 170 Watts or more from the brain.

FIG. 39 also shows a heating element 410, shown as a heating blanket.Heating blankets 410 generally are equipped with forced warm-air blowersthat blow heated air through vents in the blanket in a direction towardsthe patient. This type of heating occurs through the surface area of theskin of the patient, and is partially dependent on the surface areaextent of the patient. As shown in FIG. 39, the heating blanket 410 maycover most of the patient to warm and provide comfort to the patient.The heating blanket 410 need not cover the face and head of the patientin order that the patient may more easily breathe.

The heating blanket 410 serves several purposes. By warming the patient,vasoconstriction is avoided. The patient is also made more comfortable.For example, it is commonly agreed that for every one degree of corebody temperature reduction, the patient will continue to feelcomfortable if the same experiences a rise in surface area (skin)temperature of five degrees. Spasms due to total body hypothermia may beavoided. Temperature control of the patient may be more convenientlyperformed as the physician has another variable (the amount of heating)which may be adjusted.

As an alternative, the warming element may be any of the heating methodsproposed in U.S. patent application Ser. No. 09/292,532, filed on Apr.15, 1999, and entitled “Isolated Selective Organ Cooling Method andApparatus”, and incorporated by reference above.

Referring now to FIG. 40 is a schematic representation of an embodimentof the invention is shown, in a selective cooling version, being used tocool the brain of a patient, and to warm the blood returning from thebrain in the jugular vein. The selective organ hypothermia apparatusshown in FIG. 40 includes a first working fluid supply 420, preferablysupplying a chilled liquid such as water, alcohol or a halogenatedhydrocarbon, a first supply catheter 418 and the cooling element 102.The first supply catheter 418 has a coaxial construction. An innercoaxial lumen within the first supply catheter 418 receives coolant fromthe first working fluid supply 420. The coolant travels the length ofthe first supply catheter 418 to the cooling element 102 which serves asthe cooling tip of the catheter. At the distal end of the coolingelement 102, the coolant exits the insulated interior lumen andtraverses the length of the cooling element 102 in order to decrease thetemperature of the cooling element 102. The coolant then traverses anouter lumen of the first supply catheter 418 so that it may be disposedof or recirculated. The first supply catheter 418 is a flexible catheterhaving a diameter sufficiently small to allow its distal end to beinserted percutaneously into an accessible artery such as the femoralartery of a patient as shown in FIG. 40. The first supply catheter 418is sufficiently long to allow the cooling element 102 at the distal endof the first supply catheter 418 to be passed through the vascularsystem of the patient and placed in the internal carotid artery or othersmall artery. The method of inserting the catheter into the patient androuting the cooling element 102 into a selected artery is well known inthe art.

Although the working fluid supply 420 is shown as an exemplary coolingdevice, other devices and working fluids may be used. For example, inorder to provide cooling, freon, perfluorocarbon, water, or saline maybe used, as well as other such coolants.

The cooling element can absorb or provide over 75 Watts of heat to theblood stream and may absorb or provide as much as 100 Watts, 150 Watts,170 Watts or more. For example, a cooling element with a diameter of 4mm and a length of approximately 10 cm using ordinary saline solutionchilled so that the surface temperature of the heat transfer element isapproximately 5° C. and pressurized at 2 atmospheres can absorb about100 Watts of energy from the bloodstream. Smaller geometry heat transferelements may be developed for use with smaller organs which provide 60Watts, 50 Watts, 25 Watts or less of heat transfer.

FIG. 40 also shows a second working fluid supply 416, preferablysupplying a warm liquid such as water, a second supply catheter 414 andthe warming element 412, which can be similar or identical to thecooling element 102. The second supply catheter 414 has a coaxialconstruction. An inner coaxial lumen within the second supply catheter414 receives warm fluid from the second working fluid supply 416. Thefluid travels the length of the second supply catheter 414 to thewarming element 412 which serves as the warming tip of the catheter. Atthe distal end of the warming element 412, the fluid exits the insulatedinterior lumen and traverses the length of the warming element 412 inorder to increase the temperature of the warming element 412. The fluidthen traverses an outer lumen of the second supply catheter 414 so thatit may be disposed of or recirculated. The second supply catheter 414 isa flexible catheter having a diameter sufficiently small to allow itsdistal end to be inserted percutaneously into an accessible vein such asthe left internal jugular vein of a patient as shown in FIG. 40.

As an alternative, the warming element 412 can be an electricalresistance heater controlled by a controller represented by item 416.

Percutaneous placement of the warming element 412 into the jugular veinis accomplished directly, since the jugular vein is close to thesurface. The catheter would reside in the internal jugular and into thesuperior vena cava or even the right atrium. Jugular venous cathetersare known. As an alternative to warming of the blood in the jugular veinwith a warming element 412, a warm saline solution can be infused intothe jugular vein from a saline supply 422, via an intravenous catheter420, as shown in FIG. 41. This is advantageous since saline drips areoften necessary anyway as maintenance fluids (1000 to 2500 cc/day). Asyet another alternative, warming can be applied externally to thepatient. The means of warming can be a heating blanket applied to thewhole body, or localized heating of veins returning from the organ beingcooled. As an example, FIG. 42 shows a neck brace 426 being used toimmobilize the head of the patient. Immobilization of the head can benecessary to prevent movement of the cooling element, or to preventpuncture of the feeding artery by the cooling element. The neck brace426 can have one or more warming elements 428 placed directly over theleft and right internal jugular veins, to heat the blood flowing in thejugular veins, through the skin. The warming elements 428 can be warmedby circulating fluid, or they can be electrical resistance heaters.Temperature control can be maintained by a working fluid supply orcontroller 424.

One practice of the present invention is illustrated in the followingnon-limiting example.

Exemplary Procedure

1. The patient is initially assessed, resuscitated, and stabilized.2. The procedure may be carried out in an angiography suite or surgicalsuite equipped with fluoroscopy.3. An ultrasound or angiogram of the superior vena cava and externaljugular can be used to determine the vessel diameter and the blood flow;a catheter with an appropriately sized heat transfer element can beselected.5. After assessment of the veins, the patient is sterilely prepped andinfiltrated with lidocaine at a region where the femoral artery may beaccessed.6. The external jugular is cannulated and a guide wire may be insertedto the superior vena cava. Placement of the guide wire is confirmed withfluoroscopy.7. An angiographic catheter can be fed over the wire and contrast mediainjected into the vein to further to assess the anatomy if desired.8. Alternatively, the external jugular is cannulated and a 10-12.5french (f) introducer sheath is placed.9. A guide catheter is placed into the superior vena cava. If a guidecatheter is placed, it can be used to deliver contrast media directly tofurther assess anatomy.10. The cooling catheter is placed into the superior vena cava via theguiding catheter or over the guidewire.11. Placement is confirmed if desired with fluoroscopy.12. Alternatively, the cooling catheter shaft has sufficient pushabilityand torqueability to be placed in the superior vena cava without the aidof a guide wire or guide catheter.13. The cooling catheter is connected to a pump circuit also filled withsaline and free from air bubbles. The pump circuit has a heat exchangesection that is immersed into a water bath and tubing that is connectedto a peristaltic pump. The water bath is chilled to approximately 0° C.14. Cooling is initiated by starting the pump mechanism. The salinewithin the cooling catheter is circulated at 5 cc/sec. The salinetravels through the heat exchanger in the chilled water bath and iscooled to approximately 1° C.15. The saline subsequently enters the cooling catheter where it isdelivered to the heat transfer element. The saline is warmed toapproximately 5-7° C. as it travels along the inner lumen of thecatheter shaft to the end of the heat transfer element.16. The saline then flows back through the heat transfer element incontact with the inner metallic surface. The saline is further warmed inthe heat transfer element to 12-15° C., and in the process, heat isabsorbed from the blood, cooling the blood to 30° C. to 35° C. Duringthis time, the patient may be warmed with an external heat source suchas a heating blanket.17. The chilled blood then goes on to chill the body. It is estimatedthat less than an hour will be required to cool the brain to 30° C. to35° C.18. The warmed saline travels back the outer lumen of the catheter shaftand is returned to the chilled water bath where the same is cooled to 1°C.19. The pressure drops along the length of the circuit are estimated tobe between 1 and 10 atmospheres.20. The cooling can be adjusted by increasing or decreasing the flowrate of the saline. Monitoring of the temperature drop of the salinealong the heat transfer element will allow the flow to be adjusted tomaintain the desired cooling effect.21. The catheter is left in place to provide cooling for, e.g., 6-48hours.

In another method of use, and referring to FIG. 43, an alternativeembodiment is shown in which the heat transfer element 102 is disposedin the superior vena cava 110 from the axillary vein rather than fromthe external jugular. It is envisioned that the following veins may beappropriate to percutaneously insert the heat transfer element: femoral,internal jugular, subclavian, and other veins of similar size andposition. It is also envisioned that the following veins may beappropriate in which to dispose the heat transfer element during use:inferior vena cava, superior vena cava, femoral, internal jugular, andother veins of similar size and position.

FIG. 1 shows a cross-section of the heart in which the heat transferelement 102 is disposed in the superior vena cava 110. The heat transferelement 102 has rotating helical grooves 104 as well as counter-rotatinghelical grooves 106. Between the rotating and the counter-rotatinggrooves are bellows 108. It is believed that a design of this naturewould enhance the Nusselt number for the flow in the superior vena cavaby about 5 to 80.

Methods of Use Employing Thermoregulatory Drugs

The above description discloses mechanical methods of rewarming apatient, or portions of a patient, to minimize the deleteriousconsequences of total body hypothermia. Another procedure which may beperformed, either contemporaneous with or in place of mechanicalwarming, is the administration of anti-vasoconstriction andanti-shivering drugs. Such drugs minimize the effect of vasoconstrictionwhich may otherwise hinder heat transfer and thus cooling of thepatient. In general, hypothermia tends to trigger aggressivethermoregulatory defenses in the human body. Such drugs also prohibitresponses such as shivering which may cause damage tocardiac-compromised patients by increasing their metabolic rate todangerous levels.

To limit the effectiveness of thermoregulatory defenses duringtherapeutic hypothermia, drugs that induce thermoregulatory tolerancemay be employed. A variety of these drugs have been discovered. Forexample, clonidine, meperidine, a combination of clonidine andmeperidine, propofol, magnesium, dexmedetomidine, and other such drugsmay be employed.

It is known that certain drugs inhibit thermoregulation roughly inproportion to their anesthetic properties. Thus, volatile anesthetics(isoflurane, desflurane, etc.), propofol, etc. are more effective atinhibiting thermoregulation than opioids which are in turn moreeffective than midazolam and the central alpha agonists. It is believedthat the combination drug of clonidine and meperidine synergisticallyreduces vasoconstriction and shivering thresholds, synergisticallyreduces the gain and maximum intensity of vasoconstriction andshivering, and produces sufficient inhibition of thermoregulatoryactivity to permit central catheter-based cooling to 32° C. withoutexcessive hypotension, autonomic nervous system activation, or sedationand respiratory compromise.

These drugs may be particularly important given the rapid onset ofthermoregulatory defenses. For example, vasoconstriction may set in attemperatures of only ½ degree below normal body temperature. Shiveringsets in only a fraction of a degree below vasoconstriction.

The temperature to which the blood is lowered may be such thatthermoregulatory responses are not triggered. For example,thermoregulatory responses may be triggered at a temperature of 1½degrees below normal temperature. Thus, if normal body temperature is37° C., thermoregulatory responses may set in at 35° C. Thermoregulatorydrugs may be used to lower the temperature of the thermoregulatorytrigger threshold to 33° C. Use of the heating blankets described abovemay allow even further cooling of the patient. For example, to lower thepatient's temperature from 33° C. to 31° C., a 2° C. temperaturedifference, a 2 times 5° C. or 10° C. rise is surface temperature may beemployed on the skin of the patient to allow the patient to not “feel”the extra 2° C. cooling.

A method which combines the thermoregulatory drug methodology and theheating blanket methodology is described with respect to FIG. 44. Thisfigure is purely exemplary. Patients' normal body temperatures vary, asdo their thermoregulatory thresholds.

As shown in FIG. 44, the patient may start with a normal bodytemperature of 37° C. and a typical thermoregulatory threshold of 35° C.(step 432). In other words, at 35° C., the patient would begin to shiverand vasoconstrict. A thermoregulatory drug may be delivered (step 434)to suppress the thermoregulatory response, changing the thresholdtemperature to, e.g., 35° C. This new value is shown in step 436. Theheat transfer element may then be placed in a high flow vein, such asthe superior or inferior vena cavae or both (step 438). Cooling mayoccur to lower the temperature of the blood (step 440). The cooling maybe in a fashion described in more detail above. The cooling results inthe patient undergoing hypothermia and achieving a hypothermictemperature of, e.g., 33° C. (step 442). More cooling may be performedat this stage, but as the thermoregulatory threshold has only beensuppressed to 33° C. (step 442), shivering and vasoconstriction woulddeleteriously result. This may complete the procedure. Alternatively, anadditional drug therapy may be delivered to further lower thethermoregulatory threshold.

An alternate way to lower the thermoregulatory threshold is to use aheating blanket. As noted above, a common rule-of-thumb is that apatient's comfort will stay constant, even if their body temperature islowered 1° C., so long as a heating blanket, 5° C. warmer than theirskin, is applied to a substantial portion of the surface area of thepatient (step 444). For a 2° C.-body temperature reduction, a 10° C.(warmer than the skin temperature) blanket would be applied. Of course,it is also known that blankets warmer than about 42° C. can damagepatient's skins, this then being an upper limit to the blankettemperature. The patient's body temperature may then continue to belowered by use of a heating blanket. For each 1° C. reduction in bodytemperature (step 446), the heating blanket temperature may be raised 5°C. (step 448). After each reduction in body temperature, the physicianmay decide whether or not to continue the cooling process (step 450).After cooling, other procedures may be performed if desired (step 452)and the patient may then be rewarmed (step 454).

It is important to note that the two alternate methods ofthermoregulatory response reduction may be performed independently. Inother words, either thermoregulatory drugs or heating blankets may beperformed without the use of the other. The flowchart given in FIG. 44may be used by omitting either step 434 or steps 444 and 448.

Vasoconstrictive Therapies

FIG. 2 showed the more rapid response of the high blood flow organs tohypothermia than that of the peripheral circulation. This response maybe maintained or enhanced by applying, as an alternative method ofperforming hypothermia, a cooling blanket rather than a heating blanket.The cooling blanket may serve to vasoconstrict the vessels in theperipheral circulation, further directing blood flow towards the heartand brain.

An alternate method of performing the same function is to provideseparate vasoconstrictive drugs which affect the posterior hypothalamusin such a way as to vasoconstrict the peripheral circulation whileallowing heart and brain circulation to proceed unimpeded. Such drugsare known and include alpha receptor type drugs. These drugs, as well asthe cooling blankets described above, may also enhance counter-currentexchange, again forcing cooling towards the heart and brain. Generally,any drug or cooling blanket that provides sufficient cooling to initiatea large scale cutaneous peripheral vasoconstrictive response would becapable of forcing the cooling blood flow towards the brain and heart(i.e., the “central” volumes). In this application, the term “peripheralcirculation” or “peripheral vasculature” refers to that portion of thevasculature serving the legs, arms, muscles, and skin.

Antishiver Drugs and Regimens

Other thermoregulatory drugs are now described. Meperidine is ananalgesic of the phenyl piperidine class that is known to bind to theopiate receptor. Meperidine is also used to treat shivering due topost-operative anesthesia and hypothermia. Meperidine can also treatrigors associated with the administration of amphotericin B.

Meperidine can also be used to control shivering when hypothermia isinduced clinically. During periods of ischemia, such as occurs during astroke or heart attack, hypothermia can protect the tissue from damage.It is important to be able to cool patients with out inducing a generalanesthetic condition requiring intubation. To cool conscious patientsrequires very high doses of meperidine. Cooling of patients can beaccomplished by the above noted methods such as cooling blankets (air orwater) or alcohol bathing. Cooling can also be accomplished by bodycavity lavage (bladder, stomach, colon, peritoneal). The most efficientway to cool patients, as noted above for therapeutic purposes, is usingan intravascular catheter. An intravascular cooling catheter has a heatexchange region that is responsible for exchanging heat with the blood.Absorption of heat from the blood by the heat exchange region results incooling of the body. Causing mixing, or turbulence, on, or near, theheat exchange region, enhances heat transfer by intravascular methods.The heat exchanger of the intravascular catheter can have features thatinduce turbulence or mixing.

Shivering is regulated by the hypothalamus of the brain. Thehypothalamus regulates body temperature in general by controlling heatproduction and heat loss. Heat production above the base metabolic levelis produced through shivering, while heat loss is prevented byvasoconstriction, which decreases blood flow to the skin/periphery. Thenormothermic set point of the hypothalamus is approximately 37° C. Whenthe body is cooled a threshold is reached at which vasoconstriction andshivering occur. Vasoconstriction occurs approximately 0.5-1.0° C. belowthe set point, with shivering occurring 1.0-1.5° C. below the set point.The intensity of shivering increases proportionally with the differencefrom the threshold up to a maximum intensity. Meperidine lowers thethreshold at which shivering occurs, but it does not have much effect onthe gain and maximum intensity. The reduction of the shivering thresholdis proportional to the serum concentration of meperidine, such thatgreater serum concentrations cause a greater reduction in the threshold.Meperidine is believed to possess special antishivering effects, inparticular because it decreases the shivering threshold twice as much asthe vasoconstriction threshold. In addition, it prevents or managesshivering better than equianalgesic doses of other opioids.

Meperidine's antishivering effects (lowering of the shivering threshold)may not be related to binding of the opiate receptor. Meperidine isknown to have numerous non-opioid effects such as anticholinergic actionand local anesthetic properties. Further, the antishivering effectsproduced by meperidine are not antagonized by nalaxone, an opiatereceptor antagonist. In addition, other opiates such as morphine,pentazocine, and nalbuphine have less or no antishivering activity.Referring now to FIG. 45, the meperidine molecule 456 is structurallyvery different from the morphine 458 in FIG. 46 or morphine derivatives,which may help explain the different effects.

Meperidine usage has a number of undesirable side effects, and many arerelated to the affinity for the opiate receptor. The most serious isrespiratory sedation, which can result in death, and may be related toaffinity for the delta opiate receptor. It has been shown that blockingthe delta opiate receptor with an antagonist can reduce or eliminateopioid induced respiratory sedation. In addition, meperidine ismetabolized in the liver by n-demethylation, which produces themetabolite nor-meperidine. Nor-meperidine is known to have centralnervous system toxicity and can cause seizures. Meperidine cannot beused in patients with renal insufficiency or kidney failure due to arapid build up of the normeperidine metabolite. In addition, meperidinecannot be used in patients taking monoamine oxidase inhibitors, due tocomplications such as convulsions and hyperpyrexia.

Prodines (alpha and beta) (see FIGS. 47 and 48, molecules 460 and 462)are structurally very similar to meperidine. They too bind to the opiatereceptor, though with greater affinity. Unlike meperidine, prodines havechirality. Chiral molecules have at least one asymmetric atomic centerthat causes the mirror image of the base molecule to benon-superimposable on base molecule. Each species, the base molecule andthe mirror image, is referred to as an enantiomer.

Chiral molecules are optically active meaning each enantiomer can rotatea plane of polarized light equal but opposite directions, clockwise andcounter clockwise, plus and minus. Thus if one enantiomer rotates aplane of polarized light +10 degrees {(+) enantiomer}, the oppositeenantiomer will rotate light −10 degrees {(−) enantiomer)}. For example,the two prodines, known as alpha and beta, differ in the position of the3-methyl group. A chiral atomic center exists at the carbon to which the3-methyl group is bound and results in the various enantiomeric species.The chemical reactions that produce chiral molecules often produceracemic mixtures, or mixtures that contain fractions of each enantiomer.A racemic mixture that contains equal proportions of each enantiomer isoptically inactive.

Binding to the opiate receptor is known to be stereoselective. Thismeans that one enantiomer has much greater affinity for the receptorthan the other enantiomer. For example, the (−) isomer of morphine hasmuch greater affinity for the opiate receptor than the (+) isomer. Inthe case of alpha and beta prodine, the (+) isomer has much greateraffinity for the receptor than the (−) isomer.

It is reasonable to assume that the prodines have anti-shiver effectssimilar to meperidine due to their structural similarity. This is areasonable assumption because fentanyl (molecule 464 of FIG. 49), anopioid analgesic that is also structurally related to meperidine, alsohas anti-shiver effects. Fentanyl, also has opiate related side effectssuch as respiratory sedation.

The ideal antishiver medication or regimen would have potent antishiverefficacy with little respiratory sedation or other side effects. One wayto accomplish is to use meperidine, fentanyl, or other opioids withantishiver effects, in combination with a delta opiate receptorantagonist. Naltrindole or naltriben are competitive antagonists at thedelta receptor and can block the respiratory sedation caused byfentanyl. Thus, inducing hypothermia in a conscious patient using anintravascular cooling catheter would be accomplished using a drugregimen that included an opiate such as fentanyl or meperidine incombination with a delta receptor antagonist, such as naltrindole.

A molecule structurally similar to meperidine, but unable to bind to theopiate receptor or having antagonism at the opiate receptor, wouldlikely possess anti-shiver effects, but not opiate related respiratorysedation, since anti-shivering effects may be mediated through adifferent receptor. This ideal anti-shiver molecule exists in the formof the (−) isomer of alpha or beta prodine. The ratio of opiate efficacy(+/−) between the enantiomeric forms of alpha and beta prodine is atleast ≈10 to 30 fold. Because of the structural similarity to meperidinethey would likely retain the antishiver efficacy. In an analogousexample, dextromethorphan is a morphine-based chemical that is a coughsuppressant (antitussive). Dextromethorphan, which is the (+) methoxyenantiomer of (−) levorphanol, has retained the antitussive effects ofmorphine derivatives (i.e. (−) levorphanol), but lost other opiateeffects such as analgesia, respiratory sedation, and addiction.

In addition, the opiate receptor affinity of the (+) isomer of alpha andbeta prodine could also be interrupted. This can be accomplished byadding a hydroxyl (particularly in the m position) to phenyl ring. Thisis particularly true of the potent opiate analgesic alpha-allylprodine,in which the 3-methyl is replaced with an allyl group (see molecule 466of FIG. 50). Further, the opiate activity of (+) betaprodine isomer canbe significantly diminished by the substitution of the 3-methyl groupwith an n-propyl or allyl group. These modifications to the (+) isomersof the prodine molecules that inhibit opiate activity will not likelyeffect antishiver activity due to the structural similarity tomeperidine.

Cis-Picenadol, 1,3 dimethyl-4-propyl-4-hydroxyphenyl piperidine (cis3-methyl, 4-propyl) is phenyl piperidine compound in which the (−)enantiomer has antagonist properties at the opiate receptor (seemolecules 468 and 470 of FIGS. 51 and 52). Due to the structuralsimilarity to meperidine, this (−) enantiomer may have anti-shiveractivity with little respiratory sedation. It is known that the racemicmixture of this opioid has a ceiling effect with respect to respiratorysedation when used in animals. This ceiling effect may make racemicpicenadol a better anti-shiver drug than meperidine. Finally, tramadol(molecule 472 of FIG. 53) may have an enantiomer that has reduced opiateactivity that could lower the shiver threshold.

Alpha prodine has been used as an analgesic in clinical medicine,marketed under the trade name Nisentil. The drug is supplied as aracemic mixture. It is possible to separate the racemic mixture into twopure isomers and use the (−) isomer as an antishiver medication. Such aseparation can be accomplished using high-performance liquidchromatography (HPLC) using a chiral stationary phase. One such chiralstationary phase is cellulose-based and is supplied as Chiralcel OD andChiralcel OJ.

A representative example of the use of the novel antishiver, orthreshold lowering, drugs or regimen, is a clinical procedure to inducehypothermia in a patient. The patient would first be diagnosed with anischemic injury, such as a stroke or heart attack. An intravascularcooling catheter or a cooling blanket would be applied to the patient.The patient would be given an intravenous injection of the novel antishiver drug, such as (−) alpha prodine. Alternatively the patient couldbe given meperidine or fentanyl in combination with a delta opiatereceptor antagonist. Buspirone could be given in combination with eitherof the above regimens because it is know to enhance the antishivereffects of meperidine. The patient would be cooled to 32-35° C. orlower. During the maintenance of cooling which could last 1248 hours orlonger, doses of the antishiver drug or regimen would begin to maintaina certain plasma concentration. An infusion of the novel antishiver drugcould be used to maintain the plasma concentration. When the cooling wascomplete the patient would be rewarmed and the drugs discontinued.

Another ideal antishiver drug may be nefopam (molecule 474 of FIG. 54).Nefopam is widely used as an analgesic, particularly outside the U.S.While it is not an analog of meperidine, it has similar structural andconformational properties. For example it has a phenyl group attached toa N-methyl ring, and the phenyl group prefers the equatorial position.Similar to meperidine, nefopam is known to prevent post-operativeshivering and to prevent shivering related to Amphotericin Badministration. However, nefopam has less respiratory depression sideeffects, and is not metabolized into a neurotoxic compound. Injectablenefopam is a racemic mixture. Analgesic activity resides in the (+)enantiomer. The (−) enantiomer may be a selective anti-shiver drug andsuperior to the racemic form. Combining nefopam with intravascularcatheter based cooling induction may allow for successful implementationof therapeutic hypothermia.

It may also be desirable to use combinations of the compounds listedabove or combine them with other drugs that can reduce shivering andlower the threshold. This may lower the doses needed for either drug andreduce side effects. For example, one could combine nefopam with (−)alpha-prodine, meperidine, thorazine, buspirone, clonidine, tramadol, orother medications to achieve the desired effect. The same combinationscould be used with (−) alpha-prodine. There are many other combinationsthat could be tried including combining three agents together. Thesecombinations can be used with endovascular or surface hypothermiainduction for therapeutic purposes.

Enzyme Temperature Dependence

The above devices and techniques, including those disclosed in theapplications incorporated by reference above, provide effective coolingor heating of a fluid such as blood. The heating or cooling may occureither in the affected vessel or in a vessel in fluid communication withthe affected vessel. In this disclosure, as noted above, “fluidcommunication” between two vessels refers to a situation where onevessel either feeds or is fed by the other. One application of thesedevices and techniques is for clot lysis. However, other types of enzymeactivations may also be advantageously induced. The method disclosedbelow is applicable to other devices and techniques so long as they arealso capable of heating or cooling blood.

As noted above, enzymes have been delivered to patients in drug orintravenous form for clot lysing. These enzymes are in addition tonaturally occurring enzymes already in the blood plasma. The activity ofenzymes is at least partially adjusted by control of environmentaltemperature. A method according to an embodiment of the inventionselectively controls enzyme activity by controlling the temperature ofthe environment of the enzyme. This controlled enzyme activity allowsselective thrombolysis by selective vessel hypothermia in a mannerdescribed in more detail below.

Several experimental procedures have been reported on animals and clotpreparations at various temperatures, as disclosed below, andappropriate temperature regimes for thrombolysis may be inferred withsome accuracy. However, the mechanisms by which enzyme environmentaltemperature controls thrombolysis are not yet well characterized.Disclosed below are several suggested mechanisms. These suggestedmechanisms are conjecture, and should not be construed as limiting, inany way, the method of the invention.

The suggested mechanisms rely to a certain extent on the knownmechanisms for fibrinolysis. In particular, plasminogen is the inertprecursor of plasmin. Plasmin is an enzyme that lyses clots, i.e.,cleaves peptide bonds in fibrin. Plasminogen binds to fibrin and, whenactivated by an appropriate enzyme, such as tPA, UK, SK, etc., convertsto plasmin. Plasminogen may also be activated in solution. Inhibitorssuch as α₂-antiplasmin moderate plasmin activity by inactivating plasminreleased from a fibrin surface almost instantaneously. α₂-antiplasmincan even inactivate plasmin bound to a fibrin surface, but this processrequires about 10 seconds.

One suggested mechanism concerns the action of the inhibitors. Theactivity of α₂-antiplasmin is lessened at low temperatures and thus isless effective at inactivating plasmin. In this case, more plasmin isavailable to lyse clots and thus fibrinolysis is enhanced.

A related effect is due to the effect of plasmin levels on plasminogenlevels. Increased plasmin levels may lead to increased plasminogenlevels circulating in solution. Moreover, decreased activity ofα₂-antiplasmin also leads to increased plasminogen levels becauseα₂-antiplasmin binds plasminogen, and less α₂-antiplasmin means less ofsuch binding.

Increased plasminogen levels also suggests several other mechanisms forclot lysing.

For example, plasmin cleaves single-chain urokinase (“scu-PA” or“pro-UK”) to form UK, i.e., pro-UK is a precursor to UK. Pro-UK, liketPA, cannot efficiently activate plasminogen in solution, but it canreadily activate plasminogen bound to fibrin. Thus, increasedplasminogen, together with the body's own UK or tPA, or similar enzymesprovided intravenously, may result in more localized lysing of fibrin,e.g., directly at the clot situs.

Another suggested mechanism results from increased plasminogen. UK canactivate both plasminogen in solution and plasminogen bound to fibrin.Thus, increased plasminogen levels, together with the body's own UK, orthat provided intravenously, results in both localized lysing of fibrinand enhanced activation of plasminogen in solution.

Another suggested mechanism results from the conjectured bond of plasminin to fibrin. Plasmin may stay bound to fibrin for a longer period inthe hypothermic state. Thus, more time may be available to lyse clots,increasing overall fibrinolysis.

The hypothermic temperatures at which increased fibrinolysis occurs havenot been fully explored. However, it has been shown that clot sampleshave benefited from temperatures of, e.g., 25° C. or below. For humanpatients, it is believed that temperatures of 30° C. to 32° C. may wellbe appropriate and advantageously employed in the method of theinvention.

In a related embodiment of the invention, the method may further employa step of rewarming the cooled organ from the low temperature of, e.g.,30° C. The temperature range for rewarming may be from about 20° C. to37° C. depending on the patient, the condition, the hypothermictemperature, and so on. Rewarming has been shown to have a beneficialeffect in certain studies, perhaps by increasing the rate at which clotlysis occurs. In another related embodiment of the invention, the methodmay further employ temperature cycling the blood in the vessel from ahypothermic temperature to a rewarmed temperature. In this way, therewarming temperature regime is achieved repeatedly and thus so is theenhanced fibrinolysis.

EXAMPLE ONE Non-Drug

Researchers have studied the effect of temperature on fibrinolysis inthe context of drug studies. As part of these studies, control groupsare investigated in which no drugs are introduced. In one suchinvestigation using clot samples, clot lysis was investigated whilevarying clot temperatures in a range of 25° C. to 41° C. In the absenceof drugs, enhanced clot lysis was seen at the lower part of thetemperature range. It is believed that this study can be extended tohumans, and thus fibrinolytic activity can be enhanced at lowertemperatures.

EXAMPLE TWO Non-Drug

In another non-drug study of the effect of temperature on fibrinolysis,clot lysis in dogs was investigated while varying clot temperatures in arange of 20° C. to 36° C. The dog's temperature was lowered from anormal temperature to a low temperature. A gradual rewarming periodfollowed the low temperature period.

Enhanced clot lysis was observed at lower temperatures as compared tohigher temperatures. In particular, the maximum fibrinolytic activityoccurred in the early rewarming period, i.e., from 20° C. to about 25°C. It is believed that this study can be extended to humans, and thatfibrinolytic activity can be enhanced at lower temperatures, especiallyduring periods of rewarming.

An advantage of all of these embodiments of the method is that clotlysis can be achieved in a simple manner and without the need for drugs.An additional advantage results from the reduced temperature of theblood which helps to protect the cells from ischemia at the same timelysis is occurring. Thus, clot lysis and cooling occur simultaneously,providing an effective and aggressive dual therapy. When dual therapiesare employed, cooling catheters may be inserted in both femoral arteriesfor transit to the brain. One cooling catheter cools the brain, whilethe other cools the blood in the artery leading to the clot. The latterprovides the beneficial effects noted above.

In some cases, of course, the nature or extent of the clot is such thatlysing may only occur with drug intervention. In these cases,thrombolytic drugs, such as those disclosed above, may be introduced toinduce the fibrinolysis.

These drugs are effective at treating the thrombus. However, it may alsobe advantageous to cool the brain as a separate neuroprotective measure.The effectiveness of both therapies is enhanced when applied as soon aspossible. Thus, it is often desirable to apply both therapiessimultaneously. In this way, hypothermia is induced as a neuroprotectivemeasure, and may further induce clot lysing per se in the mannerdescribed above.

A difficulty with this approach is that the techniques areinterdependent. Drugs depend on enzymes for their activity, and enzymesare temperature-dependent. In fact, past studies have demonstrated thatthe enzyme activity of these specific thrombolytic drugs on clot samplesis temperature-dependent. In other words, their effect on clot orthrombus lysis varies over a temperature range. For typicaltemperature-specific enzymes, the greatest activity occurs at an optimaltemperature. The optimal temperature may be about 37° C. in the case ofknown thrombolytics, as this is the normal human body temperature.

Enzyme activity drastically reduces above certain temperatures as theenzyme denatures and becomes inactive. At the opposite extreme, enzymeactivity reduces below certain temperatures as the enzyme lacks theenergy necessary to couple to a substrate. Therefore, when the brain orother tissue is at a temperature different from normal body temperature,e.g., during hypothermia, an isoform of the enzyme is preferably usedwhich has an optimal working temperature at the hypothermic bodytemperature. In this disclosure, such an isoform which is effective at adifferent temperature is said to have a “working temperature” at thedifferent temperature or within a range of different temperatures.

In this disclosure, the term “isoform” of an enzyme is used as follows.If a first enzyme catalyzes a reaction at a first temperature, and adifferent enzyme catalyzes the same reaction at a second temperature,then the different enzyme is an “isoform” of the first enzyme within themeaning intended here.

For patients undergoing hypothermia, the physician may preferably use alow-temperature isoform; for patients whose temperatures have beenraised, the physician may preferably use a high-temperature isoform. Theform of the enzyme will preferably have an optimal activity curve at ornear the desired temperature. Known enzymes are described below,followed by a methodology for choosing enzymes which are not yet known.

EXAMPLE THREE Sk

Researchers have investigated the effect of temperature on thefibrinolytic activity of an SK mixture. In one such effort, clots weretreated with a mixture of plasminogen (2 mg) and SK (100 IU) in a totalvolume of 15 ml PBS. The temperature of the clots was raised from 24° C.to 37° C. These researchers found that heating enhanced the fibrinolyticactivity. In other words, heating from a hypothermic temperature tonormal body temperature increased clot lysing for clots treated with SK.

It is believed that such general trends may be extended to patientswithout lack of accuracy. Patients may be provided with a drug such asstreptokinase and may undergo hypothermia using, e.g., one of thedevices or methods described above. In particular, a cooling cathetermay be placed in an artery supplying blood to a thrombosed vessel. Thecatheter may include a separate lumen through which the SK mixture maybe delivered. A coolant or working fluid may be supplied to the coolingcatheter, causing the same to cool and to cool the blood adjacent a heattransfer element located at a distal tip of the cooling catheter. Thiscooling step may include the step of inducing turbulence in the bloodflowing through the vessel and/or in the working fluid. SK may bedelivered through the separate drug delivery lumen. The patient may thenbe rewarmed as the SK is delivered. The rewarming step may beaccomplished by passing a warm saline solution as the working fluid.

EXAMPLE FOUR tPA

Researchers have also investigated the effect of temperature on thefibrinolytic activity of tPA. Clots were treated with 2.5 μg/ml tPA andincubated at various temperatures (e.g., 37° C., 25° C., 10° C., 0° C.,and −8° C.). Plasminogen activation was relatively high at lowtemperatures (e.g., 0° C. or −8° C.) and was much less at highertemperatures. In other words, these researchers found that, for tPA,cooling to a hypothermic temperature from normal body temperatureincreased fibrinolytic activity.

As above, it is believed that such trends may be extended to patientswithout lack of accuracy. In this case, patients may be provided withtPA and may undergo hypothermia using an above device placed in anartery supplying blood to a thrombosed vessel. The catheter may includea separate lumen through which tPA may be delivered. A coolant orworking fluid may be supplied to the cooling catheter, causing thecatheter and the adjacent blood to cool. This cooling step may includethe step of inducing turbulence in the blood flowing in the vesseland/or in the working fluid. tPA may be delivered through the separatedrug delivery lumen. In this case, the patient may not be rewarmed untilthe drug delivery is complete, or until the thrombus is dissolved.

EXAMPLE FIVE tPA

Researchers have further investigated the effect of temperature on thefibrinolytic activity of tPA. Clots were treated with tPA inconcentrations of 0.3 μg/ml, 1.0 μg/ml, and 3.0 μg/ml and incubated atvarious temperatures from 24° C. to 40° C. The amount of clot lysiscorrelated with temperature at all concentrations. However, contrary tothe results indicated in Example Four, the amount of clot lysis at lowertemperatures was less than that at higher temperatures. It isconjectured that heating may have enhanced the activation of plasminogenby the tPA, and that such heating may have a similar effect in patients.This general enhancement has also been seen in UK and SK systems.

Further research is clearly necessary to determine the optimalprocedure. In any case, an embodiment of the method of the invention maybe employed to advantageously perform either heating or cooling in animproved way. To enhance the activation of plasminogen by tPA, a warmsaline solution may be provided in a catheter of the type describedabove. The warm saline solution transfers heat to the blood at a heattransfer element. An appropriate temperature range for the warm salinesolution at a point within the heat transfer element may be about 38° C.to 74° C.

EXAMPLE SIX Uk

Researchers have also investigated the effect of temperature on thefibrinolytic activity of UK. In one such effort, clots were treated witha mixture of UK at temperatures of 4° C. and 28° C. A certain amount offibrinolytic activity was induced by the introduction of the UK to theclots. Heating to 28° C. caused a second phase of activation, resultingin complete conversion of all plasminogen to plasmin, and thus increasedfibrinolytic activity. In other words, heating from a very lowtemperature (4° C.) to a hypothermic temperature (28° C.) increased clotlysing. As above, it is believed that such trends may be extended topatients. As may be noted, this Example may be analogous to that ofExample Three because of the rewarming step; a similar procedure may beemployed to perform the procedure on patients.

The above examples indicate how drugs may be combined withtemperature-altering devices as, e.g. are disclosed above, to providesimultaneous cooling and thrombolysis. This combination provides a powerdual therapy which may be advantageously employed to aggressively treatstroke and other similar body insults. When dual therapies are employed,a cooling catheter may be inserted in one femoral artery for transit tothe brain for neural protection. Of course, a heating catheter would beemployed if a temperature rise were desired. Another catheter mayprovide the drug delivery. Alternatively, the heating or coolingcatheter may have disposed therein a lumen for drug delivery. Forexample, the lumen may be coaxial with the catheter and may be disposedalong the centerline of the catheter and heat transfer element.Alternatively, the lumen may be disposed along one portion of the wallof the outlet lumen. The drug delivery lumen may have an outlet at a tipof the heat transfer element. Examples of such catheters are disclosedin U.S. patent application Ser. No. 09/215,040, filed Dec. 16, 1998, andentitled “Method and Device for Applications of Selective OrganCooling”, the entirety of which is incorporated by reference herein.These drug delivery catheters are particularly useful in dispensing thedrug or enzyme regionally, into a blood vessel containing the thrombusor into a blood vessel in fluid communication with the thrombosed bloodvessel.

The above examples have used known drugs. However, for all of the aboveand for similar techniques, an appropriate isoform of an enzyme may beemployed to allow enzymatic activity at temperatures other than normalbody temperature. One way to choose appropriate isoforms for theseenzymes is by searching for the same in cold climates. For example, SKis a bacterial enzyme. Bacteria live in many different temperatureenvironments. It is common to find or select an enzyme for a certainprocess or temperature by finding bacteria that live in environmentshaving the desired temperature.

As another example, the polymerase chain reaction is a polynucleotideamplification process that requires an enzyme capable of surviving hightemperatures. These enzymes were located in bacteria living in hotsprings and thermal vents on the sea floor. Therefore, it is likely thatcertain bacteria that live in room temperature environments orarctic-like environments will have enzymes similar to those desired,i.e., SK that can survive hypothermic environments.

tPA and UK, on the other hand, are recombinant forms of human enzymes.As such, tPA and UK could be genetically altered to maintain theiractivity at lower temperatures. For example, the protein backbone couldbe changed to yield higher tPA or UK activity at lower temperatures.

Such “temperature-specific” enzymes or drugs may be advantageously usedto localize the effect of the enzymes or drugs. Some enzymes or drugsare considered to have risks associated with their use due to total bodyeffects. For example, some thrombolytic drugs are provided onlysparingly because of the risk of hemorrhage. This risk is presentbecause current drugs are active at a working temperature which iswithin the blood temperature range of the vascular system, and becausethe drugs pervade the entire vascular system. The blood temperaturerange of the vascular system is referred to here as being within a firsttemperature range and as having an average temperature at a firsttemperature. Drugs provided to lyse thrombi also reduce clottingthroughout the vascular system, increasing the risk of hemorrhage. Ofcourse, such effects are not limited to thrombolytic drugs.

The invention provides a way to reduce such total body risks. Asdiscussed above, an appropriate isoform of an enzyme may be employed toallow enzymatic activity at temperatures other than within a normal bodytemperature range, e.g., the first temperature range described above. Inother words, for cooling, an enzyme may be found with a workingtemperature range at a hypothermic temperature. Such an enzyme may notwork within the above-described first temperature range. For example, athrombolytic isoform may lyse clots where the blood temperature ishypothermic but may not produce fibrinolytic effects where the bloodtemperature is not hypothermic.

This type of drug or enzyme may be advantageously used in the presentinvention. For example, a heat transfer element may be placed in thevasculature upstream of a vicinity in which a clot has formed. The heattransfer element may be used to cool the blood flowing to the vicinityso that the blood in the vicinity achieves a hypothermic temperature. Anisoform of a thrombolytic drug may be delivered to the vicinity, theisoform having a working temperature at the hypothermic temperature. Theisoform of the thrombolytic drug may then act to lyse the clot. Thethrombolytic drug does not produce fibrinolytic activity in portions ofthe vasculature that are not at the hypothermic temperature, i.e., therest of the body. An advantage to this method is that even very strongthrombolytics may be used to effectively lyse clots, with significantlyless concern about the above-described fibrinolytic side effectsthroughout the remainder of the body.

While the method of the invention has been described with respect tospecific devices and techniques which may be used to cool blood, othertechniques or devices may also be employed. The embodiments of themethod of the invention may advantageously employ the turbulenceinducing devices and techniques disclosed above to enhance the heattransfer and thus the heating or cooling of the blood.

Furthermore, the invention has been described predominantly with respectto a particular lysing system: the lysing of a blood clot in a bloodvessel such as is caused by stroke or myocardial infarction. However,the methods of the invention can be equally applied to altering theactivity of any enzyme relative to its activity at normal temperatures.Furthermore, the invention may be applied to cooling solids, such asvolumes of tissue, rather than blood flows or static volumes of blood.Moreover, the invention can be applied to heating blood or tissue,especially when such heating advantageously enhances desired activity ina specific enzyme.

The invention has also been described with respect to certain drugtherapies. It will be clear to one of skill in the art that variousother drugs may be employed in the method of the invention, so long asthey have characteristics similar to those described above.

Additional Therapies

Turning now from thermoregulatory drugs to additional therapies, themethod and device according to the embodiments of the invention may alsoplay a significant role in treating a variety of maladies involving celldamage. Optimal rewarming strategies for these indications are describedlater.

Stroke

A patent application incorporated by reference above discloses devicesand methods for enhancing fibrinolysis of a clot by cooling bloodflowing in an artery. The present invention may also use blood coolingto substantially reduce platelet aggregation as there is a significantreduction in platelet activity at reduced temperatures. Such reductionmay take place by inhibiting enzyme function, although the actualmethodology is unclear. This reduction in platelet aggregation, as wellas the enhanced fibrinolysis noted above, may reduce or eliminatecurrent dependence on such drugs as tPA or Rheopro.

Myocardial Infarction

The above-described venous cooling may also provide a number of benefitsfor patients undergoing myocardial infarction.

Current therapies for treating myocardial infarction involve threeareas. Thrombolysis or stenting are used to establish reflow. The oxygensupply is increased by directly supplying the patient with oxygen and byvasodilation with nitrates. And the oxygen demand is lessened bydecreasing the heart rate and the blood pressure.

Devices and methods according to the present invention can work well incombination with these current therapies. For example, the device andmethod may lessen the heart's demand for oxygen by providing cooledblood to the heart. The cooled blood in turn cools the inner chambers ofthe heart, essentially from the inside. Hearts undergoing myocardialinfarction may beat very fast due to an agitated state of the victim.However, cooled blood may induce a state of bradycardia that reduces thedemand for oxygen by the heart per se.

To establish reflow and the oxygen supply, the enhanced fibrinolysis,discussed above, may also dissolve the clot, allowing more blood flowand more oxygen delivered to the heart. As mentioned above, plateletaggregation may be reduced. Additionally, conduction through thesubendocardium, cooling the heart, may reduce the overall metabolicactivity of the heart as well as protect the subendocardium from celldamage.

It is additionally noted that reflow is often accompanied by reperfusioninjury which can further damage cells. Neutrophil activation occurs aspart of reperfusion injury. Hypothermia can limit such activation andthus can limit reperfusion injury.

Thus, numerous therapies may be delivered by one device. Therefore,e.g., currently-employed “beta-blocker” drugs used to reduce heart ratein patients undergoing infarcts may not need to be employed in patientsundergoing these hypothermic therapies.

Re-Stenosis

Another application of the device and method may be in the treatment ofstenotic arteries. Stenotic arteries are vessels that have narrowed dueto a build-up of tissue and/or plaque atheroma. Stenotic vessels aretreated by angioplasty or stenting, which opens the artery. Duringtreatment the vessel wall may be injured. Such injuries often (20-50%)cause an inflammatory reaction that eventually causes the vessel toundergo re-stenosis after a period of time, which may range from 6-12months or even several years later.

Hypothermia is known to mitigate inflammatory responses. For example,one of the initial steps in the process of re-stenosis is the migrationof macrophages or white blood cells to the injured area. Hypothermia canlimit this migration. Hypothermia can also inhibit reactions andprocesses initiated by molecules acting in an autocrine or paracrinefashion. Hypothermia may also limit the release of several growthfactors (at the site of injury) such as PDGF and EGF that act in thesefashions.

CV Rewarming/Surgery

According to one aspect of the present invention, a procedure isprovided by which a surgeon is able to perform a coronary bypassprocedure with hypothermic protection, while at the same time avoidingmany of the disadvantages associated with the use of traditionalexternal cardiopulmonary bypass systems and aortic clamping procedures.

In one embodiment of the present invention, a heat transfer element isprovided within a blood vessel of the body such that blood is cooled invivo upon contact with the heat transfer element.

The heat transfer element can be provided in either arterial or venousblood vessels. One preferred location for the heat transfer element isthe inferior vena cava, which typically ranges from 15 mm to 25 mm indiameter. A preferred method by which the heat transfer element isprovided at this position is via entry at the femoral vein

FIG. 55 is a schematic representation of the use of a heat transferelement in cooling the body of a patient. The apparatus shown in FIG. 55includes a working fluid supply 476, preferably supplying a chilledaqueous solution, a supply catheter 478 and a heat transfer element 102.The supply catheter 478 may have a substantially coaxial construction.An inner coaxial lumen within the supply catheter 478 receives coolantfrom the working fluid supply 476. The coolant travels the length of thesupply catheter 478 to the heat transfer element 102 that serves as thecooling tip of the catheter. At the distal end of the heat transferelement 102, the coolant exits an insulated interior lumen and traversesthe length of the heat transfer element 102 in order to decrease thetemperature of the surface of the heat transfer element 102. The coolantthen traverses an outer lumen of the supply catheter 478 so that it maybe disposed of or recirculated. The supply catheter 478 is a flexiblecatheter having a diameter sufficiently small to allow its distal end tobe inserted percutaneously into an accessible blood vessel, shown inFIG. 55 as the right femoral vein. The supply catheter 478 issufficiently long to allow the heat transfer element 102 at the distalend of the supply catheter 478 to be passed through the vascular systemof the patient and placed in the blood vessel of interest, here theinferior vena cava. The method of inserting the catheter into thepatient and routing the heat transfer element 102 into a selected arteryor vein is well known in the art.

In the embodiment of FIG. 55, the narrowest blood vessel encountered bythe heat transfer element as it travels to the inferior vena cava is thefemoral artery, which generally ranges from 5 to 8 mm in diameter.Accordingly, in this embodiment of the invention, the diameter of theheat transfer element is about 4 to 5 mm in diameter.

In order to obtain the benefits associated with hypothermia during acoronary bypass procedure, it is desirable to reduce the temperature ofthe blood flowing within the body to less than 35° C., more preferablybetween 30 and 35° C., and most preferably 32±2° C. Given a typicalblood flow rate of approximately 2.5 to 4 l/min, more typically about3.5 l/min, in the inferior vena cava, the heat transfer elementpreferably absorbs 200 to 300 Watts of heat when placed in this vein, inorder to induce the desired cooling effect. Approximate cooling time is15 to 30 minutes.

Cooling the body to less than 35° C. provides a number of desirableeffects. First, cooling will induce a bradycardia of the heart. Reducedheart rates corresponding to about ⅔ of the normal heart rate are commonat the preferred temperature of 32±2° C. By slowing the beating of theheart, the present invention facilitates surgery during beating heartprocedures. Such procedures are well known in the art. For example, theperformance of coronary surgery on the beating heart is described byBenetti et al in “Coronary Revascularization With Arterial Conduits Viaa Small Thoracotomy and Assisted by Thoracoscopy, Although WithoutCardiopulmonary Bypass”, Cor. Europatum, 4(1): 22-24 (1995), and byWestaby, “Coronary Surgery Without Cardiopulmonary Bypass” in the March,1995 issue of the British Heart Journal. Additional discussion of thissubject matter can be found in Benetti et al, “Direct myocardialrevascularization without extracorporeal circulation. Experience in 700patients”, Chest, 100(2): 312-16 (1991), Pfister et al, “Coronary arterybypass without cardiopulmonary bypass” Ann. Thorac. Surg., 54:1085-92(1992), and Fanning et al, “Reoperative coronary artery bypass graftingwithout cardiopulmonary bypass”, Ann. Thorac. Surg., 55:486-89 (1993).Each of the above articles is hereby incorporated by reference.

Moreover, the general anesthesia associated with coronary bypasstechniques is often accompanied by vasodilation in the patient whichdecreases organ perfusion and hence increases the risk of ischemia. Thiseffect, however, is combated by the hypothermia induced in accordancewith the present invention, which promotes vasoconstriction.

Cooling the body also protects the organs from ischemic damage due tolow circulatory flow rates or due to emboli formation. For example, aspreviously noted, procedures are known in the art in which (1) the heartis intermittently stopped and restarted or (2) the heart is stopped anda small intracorporeal pump is used to provide circulatory support.These techniques and others like them allow the surgeon to operate on astill or nearly still heart. However, each of these techniques alsoplaces the patient at risk from ischemia. By lowering the bodytemperature of the patient to a preferred temperature of 32±2° C. inaccordance with the present invention, however, the oxygen demand of thebodily tissue, and hence the danger of ischemia associated with theseprocedures, is reduced.

More specifically, with some techniques in which alternating periods ofheartbeat and heart arrest are provided, the heart is stopped or nearlystopped using drugs such as beta-blockers, and a pacing device is usedto cause the heart to beat on demand. An example of one such system isthe TRANSARREST system; Corvascular, Inc., Palo Alto, Calif. In othertechniques, the heart is momentarily stopped or slowed by electricallystimulating the vagus nerve. See, e.g., U.S. Pat. Nos. 5,913,976 and6,006,134, the disclosures of which are hereby incorporated byreference. (As noted in U.S. Pat. No. 5,913,876, one or more heartpacing devices, such as a Pace port-Swann pulmonary artery catheter, maybe inserted in conventional fashion to the patient's heart and used torestore the beating of the heart during the surgery, in the event theheart is slow to revive after a nerve stimulating signal is turned off.)Each of these techniques is associated with a circulatory flow rate thatcan be significantly lower than normal cardiac output.

The risks of ischemia due to low circulatory flow rates, however, arereduced in accordance with an embodiment of the invention. Inparticular, before manipulating the heartbeat of the patient, a heattransfer element is inserted into the vasculature of the patient and thebody temperature of the patient is reduced, preferably to 32±2° C. Asnoted above, by lowering the body temperature, the body's oxygen demandis reduced, decreasing the risk of ischemia. Moreover, a reduction inbody temperature in accordance with the present invention is accompaniedby vasoconstriction, which decreases the circulatory flow rate that isrequired for adequate organ perfusion and consequently further decreasesthe risk of ischemia.

The present invention is also useful in connection with techniques inwhich the heart is stopped or nearly stopped and an intracorporeal pumpis used to support circulation. For example, techniques are known inwhich circulatory support is provided during coronary bypass by a pumppositioned in the patient's aortic valve. See, for example, M. S.Sweeney, “The Hemopump in 1997: A Clinical, Political, and MarketingEvolution”, Ann. Thorac. Surg., 1999, Vol. 68, pp. 761-3, the entiredisclosure of which is hereby incorporated by reference. In thisreference, a coronary bypass operation is described in which esmolol, ashort acting beta-blocker, is administered to calm the heart duringsurgery. A Medtronic Hemopump® is used for circulatory support and thepatient's own lungs are used for oxygenation. At the core of theHemopump is a small, rapidly turning Archimedes screw. The pump assemblyis made of stainless steel and is attached to a silicone rubber inletcannula. The cannula is positioned across the aortic valve and into theleft ventricle. The pump assembly is catheter mounted to facilitateplacement of the pump in its operating position. For example, the pumpassembly is ordinarily inserted into the femoral artery of the thigh,whereupon it is guided to the left ventricle. Once in place, the cannulaacts to entrain blood and feeds it to the pump portion, which then pumpsthe blood into circulation via the aorta. The pump is operated by thecreation of pulsing electromagnetic fields, which cause rotation of apermanent magnet, resulting in operation of the Archimedes screw.Electrical power is provided from a console outside the patient. Thepumping action is axial and continuous (i.e., non-pulsatile). Due to thedesign of the Hemopump, rotational speeds on the order of 10,000 to20,000 rpm can be used to produce blood flow of about four liters perminute or less (depending on the model) without significant hemolysis.Additional details are found in M. C. Sweeney and O. H. Frazier,“Device-supported myocardial revascularization; safe help for sickhearts”: Ann. Thorac. Surg. 1992, 54: 1065-70 and U.S. Pat. No.4,625,712, the entire disclosures of which are hereby incorporated byreference.

This technique and others like it, however, are frequently associatedwith circulatory flow rates (i.e., about 4 l/min or less) that are lowerthan normal cardiac output (i.e., about 5 l/min for many people) placingthe patient at ischemic risk. By lowering the body temperature of thepatient to a preferred range of 32±2° C. in accordance with the presentinvention, however, the blood vessels are constricted and oxygen demandof the bodily tissue is reduced, increasing organ perfusion and reducingthe danger of ischemia for a given circulatory output.

As noted above, in a preferred embodiment of this first aspect of theinvention, the heat transfer element is provided in the inferior venacava, which is accessed via the femoral vein. In contrast, the Hemopumpis preferably provided in the left ventricle, which is accessed via thefemoral artery. In this way, both the heating element and the Hemopumpcan be concurrently placed in the body in a minimally invasive fashion.

According to another aspect of the invention, a hypothermic medicalprocedure is performed on a patient in a conscious or semiconsciousstate. An example of a situation where such a hypothermic medicalprocedure may be performed is one in which a patient has suffered astroke and hypothermia is induced in the brain to reduce ischemicdamage.

Such procedures can be performed either to cool the entire body of thepatient or a region within the patient's body, typically an organ.

The entire body can be cooled using the procedures discussed above. Forexample, the heat transfer element is preferably provided in a venousblood vessel, more preferably the inferior vena cava, to effect coolingof the entire body.

In order to intravascularly regulate the temperature of a selectedregion, the heat transfer element may be placed in a feeding artery ofthe region to absorb or deliver the heat from or to the blood flowinginto the region. The heat transfer element should be small enough to fitwithin the feeding artery while still allowing a sufficient blood flowto reach the region in order to avoid ischemic damage. By placing theheat transfer element within the feeding artery of a region, thetemperature of the region can be controlled, while having less effect onthe remaining parts of the body. Using the brain as an example, thecommon carotid artery supplies blood to the head and brain. The internalcarotid artery branches off of the common carotid to directly supplyblood to the brain. To selectively cool the brain, the heat transferelement is placed into the common carotid artery, or both the commoncarotid artery and the internal carotid artery. The internal diameter ofthe common carotid artery ranges from 6 to 8 mm and the length rangesfrom 80 to 120 mm. Thus, the heat transfer element residing in one ofthese arteries cannot be much larger than 4 mm in diameter in order toavoid occluding the vessel, which would result, for example, in ischemicdamage.

When hypothermia is induced in a patient, less than desirable sideeffects can occur in the patient. For example, hypothermia is known toactivate the sympathetic nervous system in a conscious or semiconsciouspatient, resulting in a significant norepinephrine response.Norepinephrine, in turn, binds to beta sites including those in theheart, causing the heart to beat harder and more rapidly, frequentlyresulting in cardiac arrhythmia and increased risk of myocardialischemia. In accordance with an embodiment of the present invention,however, a beta-blocker is administered to the patient. Without wishingto be bound by theory, it is believed that the beta-blocker offsets thenorepinephrine binding noted above. In general, the beta-blocker may beadministered before the patient cooling commences, and preferablyimmediately before patient cooling commences.

Preferred beta-blockers for this aspect of the invention include β1blockers, β1β2 blockers and β1β2 blockers. Preferred β1 blockers includeacebutolol, atenolol, betaxolol, bisoprolol, esmolol and metoprolol.Preferred β1β2 blockers include carteolol, nadolol, penbutolol,pindolol, propranolol, sotalol and timolol. Preferred β1β2 blockersinclude carvedilol and labetalol.

The heightened demand that hypothermia places on the heart of consciousor semiconscious patents may also be relieved, for example, with heatingblankets. However, vasoconstriction limits the heating ability of theheating blankets. Without wishing to be bound by theory, it is believedthat the above-noted production of norepinephrine activatesalpha-receptors, for example, in the peripheral blood vessels, causingthis vasoconstriction. The vasoconstriction can be offset, in accordancewith the present invention, by treating the patient with alpha-blockerswhen indicated, preferably before cooling is initiated. Preferredalpha-blockers include labetalol and carvedilol.

In the various embodiments of the invention, once the medical procedureis completed, the heat transfer element is preferably used to warm thebody back to its normal temperature, i.e., 37° C.

According to another aspect of the present invention, a procedure isprovided in which hypothermia is induced in a human patient in need ofneural protection due to ischemic neural conditions by positioning aheat transfer element in a blood vessel of the patient. To enhance theneural protection provided by the induced hypothermia, an effectiveamount of one or more therapeutic agents is administered to the patient,which therapeutic agents may include (a) an antipyretic agent, (b) afree-radical scavenger, and/or (c) an N-methyl-D-aspartame receptorantagonist.

Preferred antipyretic agents for the purposes of the present inventionare antipyretic agents having anti-inflammatory properties as well asantipyretic properties, such as dipyrone. Dipyrone has been withdrawn orremoved for the market in the U.S., but it is available from Hoechst AG. Determining the dosage forms, dosage amounts and dosage frequenciesthat are effective to supplement the neural protection provided byhypothermia is well within the abilities of those of ordinary skill inthe art. In the event that the ischemic neural conditions are associatedwith fever, such as that commonly associated with stroke, theantipyretic agent is administered until the risk of fever subsides,typically at least three days after hypothermia is suspended.

Preferred free radical scavengers for the purposes of the presentinvention include tirilazad or any pharmaceutically active saltsthereof. Tirilazad mesylate, which is both a free-radical scavenger anda lipid peroxidation inhibitor, is manufactured by Upjohn under thetrade name FREEDOX and is indicated to improve survival and functionaloutcome in male patients with aneurismal subarachnoid hemorrhage.Determining those dosage forms, dosage amounts and dosage frequenciesthat are effective to supplement the neural protection provided byhypothermia is well within the abilities of those of ordinary skill inthe art.

Preferred N-methyl-D-aspartame receptor antagonists for the practice ofthe present invention include dextrometliorphan, MgCl₂ and memantine,more preferably dextromethorphan and pharmaceutically active salts ofthe same. Dextromethorphan is commonly found in syrup form and isavailable from a variety of sources. A preferred dosage fordextromethorphan is 10 to 30 mg orally every four to eight hours for atleast three days. Determination of other appropriate dosage forms,dosage amounts and dosage frequencies that are effective to supplementthe neural protection provided by hypothermia is well within theabilities of those of ordinary skill in the art.

Combinations of the above therapeutic agents are also possible. Forexample, in one preferred embodiment, a free radical scavenger and anN-methyl-D-aspartame receptor antagonist are co-administered along withthe hypothermia.

The method of the present invention is appropriate for various types ofischemic neural conditions, including ischemia of the spinal cord,cerebral ischemia including stroke, and so forth.

The need for neural protection due to ischemic neural conditions canoccur in various contexts. In some instances, a patient has experiencedan unanticipated ischemic injury, for example, due to physical trauma,such as that associated with an automobile accident, or due to apathological event, such as a stroke. Under such circumstances, it ispreferred that hypothermia be induced and therapeutic agent be appliedwithin 6 to 12 hours after the patient has experienced the ischemicinjury.

In other instances, the patient is at risk of ischemic neural conditionsdue to a medical procedure such as cardiac surgery, brain surgeryincluding aneurysm surgery, and so forth. In these instances, it ispreferred that hypothermia be induced and that the therapeutic agent beadministered before to the medical procedure commences.

In addition, in some applications, it may be advantageous to attach astent to the distal end of the heat transfer element. The stent may beused to open arteries partially obstructed by atheromatous disease priorto initiation of heat transfer. Further, the device may be used todeliver drugs such as blood clot dissolving compounds (e.g., tissueplasminogen activator (“tPA”), urokinase, pro-urokinase, streptokinase,etc.) or neuroprotective agents (e.g., selective neurotransmitterinhibitors). In addition to therapeutic uses, the device may be used todestroy tissue such as through cryosurgery.

Fever

A one or two-step process and a one or two-piece device may be employedto intravascularly lower the temperature of a body in order to treatfever. A cooling element may be placed in a high-flow vein such as thevena cavae to absorb heat from the blood flowing into the heart. Thistransfer of heat causes a cooling of the blood flowing through the heartand thus throughout the vasculature. Such a method and device maytherapeutically be used to treat fever.

A heat transfer element that systemically cools blood should be capableof providing the necessary heat transfer rate to produce the desiredcooling effect throughout the vasculature. This may be up to or greaterthan 300 watts, and is at least partially dependent on the mass of thepatient and the rate of blood flow. Surface features may be employed onthe heat transfer element to enhance the heat transfer rate. The surfacefeatures and other components of the heat transfer element are describedin more detail below.

One problem with treating fever with cooling is that the cause of thepatient's fever attempts to defeat the cooling. Thus, a high powerdevice is often required.

Of course, the use of the superior vena cava is only exemplary. It isenvisioned that the following veins may be appropriate to percutaneouslyinsert the heat transfer element: femoral, internal jugular, subclavian,and other veins of similar size and position. It is also envisioned thatthe following veins may be appropriate in which to dispose the heattransfer element during use: inferior vena cava, superior vena cava,femoral, internal jugular, and other veins of similar size and position.Arteries may also be employed if a fever therapy selective to aparticular organ or region of the body is desired.

In a method according to an embodiment of the invention for treatingpatients with fever, the heat transfer element as described may beplaced in any of several veins, including the femoral, the IVC, the SVC,the subclavian, the braichioceplialic, the jugular, and other suchveins. The heat transfer element may also be placed in appropriatearteries for more selective fever reduction.

The amount of cooling performed may be judged to a first approximationby the rate of cool-down. The amount of cooling is proportional to thedifference between the temperature of the blood and the temperature ofthe heat transfer element or cooling element. Thus, if the temperatureof the blood is 40° C. and the temperature of the cooling element is 5°C., the power extracted will be greater than if the temperature of theblood is 38° C. and the temperature of the cooling element is maintainedat 5° C. Thus, the cool-down or cooling rate is generally greatest atthe beginning of a cooling procedure. Once the patient temperaturebegins to approach the target temperature, usually normothermia or 37°C., the cooling rate may be reduced because the temperature differentialis no longer as great.

In any case, once the patient reaches the normothermic temperature, itis no longer easy to guess whether, in the absence of the coolingtherapy, the patient would otherwise be feverish or whether the feverhas abated. One embodiment of the invention allows a determination ofthis.

First, it is noted that the power extracted can be calculated from thetemperature differential between the working fluid supply temperatureand the working fluid return temperature. In particular:

P_(catheter)=Mc_(f)ΔT_(f)

Where P_(catheter) is the power extracted, M is the mass flow rate ofthe working fluid, c_(f) is the heat capacity of the working fluid, andΔT is the temperature differential between the working fluid as itenters the catheter and as it exits the catheter. Accordingly,P_(catheter) can be readily calculated by measuring the mass flow of thecirculating fluid and the temperature difference between the workingfluid as it enters and exits the catheter. The power removed by thecatheter as determined above may be equated to a close approximation tothe power that is lost by the patient's body.

In general, a closed-form solution for the power P required to cool (orheat) a body at temperature T to temperature T₀ is not known. Onepossible approximation may be to assume an exponential relationship:

P=α(exp β(T−T _(o))−1)

Taking the derivative of each side with respect to temperature:

$\frac{\partial P}{\partial T} = {\alpha \; \beta \; ^{\beta {({T - T_{0}})}}}$

and taking the inverse of each side:

$\frac{\partial T}{\partial P} = \frac{1}{\alpha \; \beta \; ^{\beta {({T - T_{0}})}}}$or${\Delta \; T} \approx {\frac{\partial T}{\partial P}\Delta \; P}$

where ΔT is the temperature differential from nominal temperature and ΔPis the measured power.

A close approximation may be obtained by assuming the relationship islinear. Equivalently, a power series expansion may be taken, and thelinear term retained.

In any case, integrating, assuming a linear relationship, andrearranging:

P=α(T−T ₀),

where the constant of proportionality has units of watts/degree Celsius.One can determine the constant of proportionality α using two pointsduring the therapy when both T and P are finite and known. One may bewhen therapy begins, i.e., when the patient has temperature T and thecatheter is drawing power P. Another point may be obtained when T=T₀ andP=P₀.

Then, for any P, T is given by:

$T_{{absence}\mspace{14mu} {of}\mspace{14mu} {therapy}} = {T_{0} + \frac{P_{{at}\mspace{14mu} T_{0}}}{\alpha}}$

An example of this may be seen in FIG. 56, which shows a flowchart of anembodiment of a method of the invention. Referring to the figure, apatient presents at a hospital or clinic with a fever (step 480).Generally, such a patient will have a fever as a result of a malady orother illness for which hospitalization is required. For example, themajority of patients in ICUs present with a fever.

A catheter with a heat transfer element thereon may be inserted (step482). The initial power withdrawn P_(start) and body temperatureT_(start) may be measured (step 484), and the therapy begun (step 486).The therapy continues (step 488), and P and T are periodically,continuously, or otherwise measured (step 490). The measured T iscompared to the normothermic T=T₀, which is usually about 37° C. (step492). If T is greater than T0, the therapy continues (step 488). If T isless than T₀, then the power P₀ is measured at T=T₀ (step 494). By theequations above, a constant of proportionality a may be uniquelydetermined (step 496) by knowledge of T_(start), P_(start), P₀, and T₀.From α, T_(start), P_(start), P₀, and T₀, T_(absence of cooling) may bedetermined (step 498). T_(absence of cooling) is then compared to T₀(step 500). If T_(absence of cooling)>T₀, then the patient is stillgenerating enough power via their metabolism to cause a fever if thetherapy were discontinued. Thus, therapy is continued (step 502). IfT_(absence of cooling)<=T₀, then the patient is no longer generatingenough power via their metabolism to cause a fever if the therapy werediscontinued. Thus, therapy is discontinued (step 504). Variations ofthe above method will be apparent to those of ordinary skill in the art.The manifold of the present invention is generally shown at 506 in FIG.57. The manifold 506 is connected at its distal end 508 to a three lumencatheter 104 that circulates fluid for any of a variety of medical andtherapeutic purposes. However, for purposes of discussion only, thepresent invention will be described in terms of a heat transfer catheterin which fluid is circulated through the catheter to cool or heat thewhole body or a selected portion of a patient. A strain relief sleeve514 protects the catheter 512 from kinking immediately adjacent to thedistal end 508 of the manifold 506.

The three lumen catheter 512, as shown in FIG. 58, has an outer tube530, an intermediate tube 538 and an inner tube 534. The catheter has aguide wire space or lumen 540 defined by the inner surface of inner tube534. An outer annular lumen 542 is defined between the inner surface ofouter tube 530 and the outer surface of intermediate lumen 538. An innerannular lumen 536 is defined between the inner surface of intermediatetube 538 and the outer surface of the inner tube 534.

In operation, once the catheter 512 is in place, a working fluid such assaline or other aqueous solution may be circulated through the catheter512. Fluid flows up the inner annular lumen 536. At the distal end ofthe catheter 512, the working fluid exits the inner annular lumen 536and enters outer annular lumen 542. If the catheter 512 is employed totransfer heat, it may be constructed from a highly conductive materialso that the temperature of its external surface may reach very close tothe temperature of the working fluid. In order to avoid the loss ofthermal energy from the working fluid within the inner annular lumen536, an insulating coaxial layer may be provided within the coolingcatheter 512. In some cases a substantial portion of the entire lengthof the outer annular lumen 542 may be insulated except at one or moreparticular locations through which heat is to be directly applied to theportion of the body in contact therewith.

Referring again to FIG. 57, the manifold 506 includes a first manifold518, which provides access to the inner annular lumen 536 via port 524.The manifold 506 also includes a second manifold 516, which providesaccess to the outer annular lumen 542 via port 522. The first manifold518 also includes a guide wire entry port 526, which provides access tothe guide wire lumen 540 for a guide wire (not shown). When installed,the guide wire generally follows the central axis 521 through themanifold. As shown, guide wire entry port 526 may be tapered so that theguidewire can be easily inserted without damage. The first manifold 518has a proximal end 510 on which a Luer fitting 520 is located.

Console

With reference to FIG. 59, an embodiment of a heat transfer cathetersystem 544 includes a heat transfer catheter 546, a control system 548,and a circulation set 550 housed by the control unit system 548. Thecontrol system 548 may be equipped with an output display 552 and inputkeys 554 to facilitate user interaction with the control system 548. Ahood 556 is pivotally connected to a control unit housing 558 forcovering much of the circulation set 550.

With reference additionally to FIGS. 60 and 61, in a preferredembodiment, the catheter 568 is a heat transfer catheter such as, butnot by way of limitation, a hypothermia catheter capable ofintravascular regulation of the temperature of a patient's body or oneor more selected organs. The catheter 568 may include a heat transferelement 562 located at a distal portion thereof. In the embodiment ofthe heat transfer element shown, the heat transfer element 562 includesa supply lumen 564 and a return lumen 566. The supply lumen 564 andreturn lumen 566 preferably terminate at respective distal points in adistal portion of the heat transfer element 562 and terminate atrespective proximal points at a supply lumen port 570 and a return lumenport 572 in catheter handle 573.

The heat transfer element 562 may be placed in the vasculature of thepatient to absorb heat from or deliver heat to surrounding blood flowingalong the heat transfer element 562, thereby regulating the temperatureof a patient's body or one or more selected organs. In an analogousfashion, the heat transfer element 562 may be used within a volume oftissue to regulate the tissue temperature by absorbing heat from ordelivering heat to a selected volume of tissue. In the latter case, heattransfer is predominantly by conduction.

In an exemplary application, the heat transfer catheter 568 may be usedto cool the brain. One or more other organs, as well as the whole body,may also be cooled and/or heated, i.e., temperature controlled. Thecommon carotid artery supplies blood to the head and brain. The internalcarotid artery branches off the common carotid artery to supply blood tothe anterior cerebrum. The heat transfer element 562 may be placed intothe common carotid artery or into both the common carotid artery and theinternal carotid artery via the femoral artery or other well knownvascular routes. Heat transfer fluid supplied, chilled, and circulatedby the circulation set 550 causes the heat transfer element 562 to drawheat from the surrounding blood flow in the carotid artery or internalcarotid artery, causing cooling of the brain to, for example, reduce theeffects of certain body injuries to the brain.

Although the catheter 568 has been described as including a specificheat transfer element 562, it will be readily apparent to those skilledin the art that the circulation set of the present invention may be usedwith heat transfer catheters including heat transfer elements other thanthe specific heat transfer element 562 described above. Further,although the circulation set 550 is described in conjunction with a heattransfer catheter, it will be readily apparent to those skilled in theart that the circulation set of the present invention may be used inconjunction with catheters other than hypothermia or heat transfercatheters. For example, the circulation set may be used with cathetersthat require a fluid to be supplied to and/or circulated through thecatheter.

Circulation Set

With reference to FIGS. 59 and 62, an embodiment of the circulation set550 will now be described. The circulation set 28 550 include one ormore of the following: a fluid reservoir 574, a pump 576, a filter 578,a heat exchanger 580, a temperature and pressure sensor assembly 584, asupply line 586, and a return line 588. The supply lumen port 570 andreturn lumen portion are coupled with respective supply lines 586 andreturn lines 588 of the circulation set 550. The supply line 586 andreturn line 588 are preferably comprised of one or more pieces oftubing, connectors, etc. for joining the aforementioned components ofthe circulation set 550 to the supply lumen port 570 and return lumenport 572. The circulation set 550 may supply, filter, circulate, and/orbe used to monitor the temperature and pressure of the heat transferfluid for the catheter 546. Each of these components will now bedescribed in turn.

Fluid Reservoir

In a preferred embodiment, the fluid reservoir 60 is a modified 250 mlIV bag made of PVC. The fluid reservoir 574 may be filled with a workingfluid such as, but not by way of limitation, saline, freon, orperfluorocarbon. In order to prevent the working fluid from causing EMIinterference with other electronic devices used in the operating room,the working fluid may be a non-ionic fluid such as, but not by way oflimitation, D5W, D5W with 1.5% glycerine, Sorbitol-Mannitol, andRinger's Solution.

The fluid reservoir 574 may be used to prime the lines 586, 588 andlumens 564, 566 of the system 544. The fluid reservoir 574 includes asupply or inlet tube 590 that communicates at an inlet 592 with thereturn line 588 and communicates at an opposite end or outlet 594 withan inside 596 of the reservoir 574. The fluid reservoir 574 alsoincludes a return or outlet tube 598 that communicates at one end withthe supply line 586 and communicates at an opposite end or inlet 602,with the inside 596 of the reservoir 574.

The fluid reservoir 574 preferably also includes a mechanism 604 forpurging, venting or removing air from the system 544. The air purgingmechanism is used to remove air from the lines 586, 588 and lumens 564,566 of the system 544 and, in a preferred embodiment, includes aneedleless polycarbonate valve 606 with a polycarbonate vented spike608. The removal or purging of air from the system 544 is important formaximizing the pressure in the system 544, maximizing heat transfer atthe heat transfer element 562, and preventing air from possibly enteringthe blood stream of the patient caused by a break or leak in thecatheter 568. The outlet 594 of the supply tube 590 may be locatedcloser to the air purging mechanism 604 than the inlet 602 of the returntube 598 or adjacent to the air purging mechanism 604 to inhibit airbubbles supplied by the supply tube 590 from directly entering thereturn tube 598 without the opportunity to be removed by the air purgingmechanism 604. The purging cycle will be discussed in greater detailbelow.

In an alternative embodiment of the circulation set, the fluid reservoir574 may supply or prime the system 544 without recirculation of workingfluid therethrough. In this embodiment, the reservoir 574 may notinclude the supply tube 590 and the air removal mechanism 604. The airremoval mechanism 604 may be located in the circulation set 550 outsideof the fluid reservoir 574.

The pump 576 is may be a disposable, plastic micro-pump that is disposedof or discarded with the other disposable components of the circulationset 550 after a single use. The pump 576 is used to draw the heattransfer fluid from the fluid reservoir and circulate the fluidthroughout the lines 586, 588 and lumens 564, 566. In an alternativeembodiment, the pump may be a permanent, non-disposable pump.

Filter

The filter 578 is preferably a 5 micron filter carried by male andfemale housing members. The filter 578 removes impurities from thecirculating heat transfer fluid. In other embodiments of the circulationset 550, the circulation set 550 may include more than one filter 578,the circulation set 550 may include no filters 578, or the filter 578may be a part of one or more components of the circulation set 550.

Heat Exchanger

In the embodiment of the circulation set illustrated in FIGS. 59 and 62,the heat exchanger 580 is a stainless steel tubing 582 that sits in abath 560 of a second heat transfer fluid made of a biocompatible fluidsuch as, but not limited to, galden or ethylene glycol. This is anexample of a wet heat exchanger because the tubing 5892 resides within aliquid heat transfer fluid. A second heat exchanger (not shown) locatedin the control unit housing 558 regulates the temperature of the bath560 for controlling the temperature of the heat transfer fluid in thesystem 544. The heat exchanger 580 is a reusable, non-disposable, wetheat exchanger.

With reference to FIGS. 63-66, an embodiment of a dry heat exchanger 610including a disposable, single-use heat exchanger member 612 may be usedin the circulation set 550. The heat exchanger member 612 is removablysecurable within heat exchanger mold members 614, 616.

The heat exchanger mold members 614, 616 are preferably constructed of athermoplastic insulative material and may include matching, mirroredserpentine grooves 618 therein. The serpentine grooves 618 terminate atone end in an inlet groove 620 and terminate at an opposite end in anoutlet groove 622. The inlet groove 620 and outlet groove 622accommodate inlet tube 626 and outlet tube 628 of the disposable heatexchanger member 612 and corresponding connection tubes (not shown) forconnecting to the supply line 586. In an alternative embodiment, eachheat exchanger mold member 614, 616 may have more than one inlet and/oroutlet. Instead of serpentine grooves 618, each heat exchanger moldmember may include one or more cavities that form reservoirs that heattransfer fluid flows through. First and second heat exchanger surfaces624, 632 are located on inner faces of the mold members 614, 616. In apreferred embodiment, the heat exchanger surfaces 624, 632 are stampedstainless steel pieces of sheet metal that are bonded to the inner facesof the mold members 614, 616 so as to form heat transfer paths 634 (FIG.64) therebetween. The heat exchanger surfaces 624, 632 preferably haveserpentine grooves 636 stamped therein. In an alternative embodiment ofthe invention, each groove 636 may have a shape that is other thanserpentine or there may be more or less channels in each serpentinegroove 636. The heat exchanger surfaces 624, 632 isolate the disposableheat exchanger member 612 from the heat transfer fluid flowing throughthe heat transfer paths 634, making the heat exchanger a “dry” heatexchanger in that the heat transfer fluid, e.g., ethylene glycol, doesnot contact the external surface of the disposable heat exchanger member616.

The disposable heat exchanger member 612 is preferably constructed of anIV bag and may include the aforementioned inlet tube 626 and outlet tube628 welded to a bag body 630.

In use, the heat exchanger 610 is opened by separating the first heatexchanger mold member 614 and the second heat exchanger mold member 616,the disposable heat exchanger member 612 is placed therebetween, and theheat exchanger 610 is closed by bringing the first heat exchanger moldmember 614 and the second heat exchanger mold member 616 together. Whenthe heat exchanger 610 is closed, the disposable heat exchanger member612 conforms to the shape of the serpentine grooves 636, formingcorresponding serpentine fluid passages 638 in the disposable heatexchanger member 612. As working fluid flows through the serpentinepassages 638, heat transferred between the heat transfer fluid in theheat transfer paths 634 and heat exchanger surfaces 624, 632 causescorresponding heat transfer between the heat exchanger surfaces 624, 632and the working fluid in the serpentine passages 638. After use, theheat exchanger member 610 is opened by separating the first heatexchanger mold member 614 and the second heat exchanger mold member 616,and the disposable heat exchanger member 610 is disposed of with therest of the disposable components of the circulation set 550.

Thus, the heat exchanger 610 is a dry heat exchanger because theexternal surface of the disposable heat exchanger member 610 does notcontact a liquid, making it not as messy as the aforementioned coiledheat exchanger 580 that resides in a liquid bath. The heat exchangermember 612 is inexpensive and conveniently disposable after a singleuse.

In alternative embodiments of the invention, the heat exchanger may havea different construction. For example, a pair of heat exchangers 610 maybe stacked on each other in a “double-decker” fashion, sharing a commonheat exchanger mold member, the disposable heat exchanger member 610 mayinclude a bag with serpentine or other-shaped passages already formedtherein, or the disposable heat exchanger member 610 may be comprised ofa stainless steal tube shaped in serpentine or other pattern.

Temperature and Pressure Sensor Assembly

With reference to FIGS. 67-70, the temperature and pressure sensorassembly 584 will now be described in more detail. The temperature andpressure sensor assembly 584 is used for measuring the temperature andthe pressure of the heat transfer fluid in the supply line 586 before itenters the catheter 568, and measuring the temperature and the pressureof the heat transfer fluid in the return line 588, after it leaves thecatheter 568. These measurements are important for determining thepressure of the heat transfer fluid flowing through the catheter 568 andthe heat transfer that occurs at the heat transfer element 562 of thecatheter 568. Heating or cooling efficiency of the heat transfer element562 is optimized by maximizing the pressure or flow rate of workingfluid through the catheter. Although the assembly 584 is described as atemperature and pressure assembly, the assembly 584 may be used tomeasure only temperature or pressure. Further, the assembly 584 may beused for measuring other physical characteristics of the working fluid.

The temperature and pressure sensor assembly 584 includes two maincomponents, a multi-use, fixed, non-disposable temperature and pressuresensor electronics member 640 and a single-use, disposable temperatureand pressure sensor block member 642.

With reference to FIGS. 67-68, the temperature and pressure sensorelectronics member 640 includes a base 644 and a latch 646 pivotallycoupled thereto by a pin 648. The base 644 includes an upper surface 664and a skirt 666 that together define a receiving area 668 for thetemperature and pressure block member 642. The base 644 includes firstand second round pressure transducer holes 670, 672 that receivecorresponding first and second pressure transducers 674, 676 and firstand second round thermocouple holes 678, 680 that receive correspondingfirst and second thermocouples 682, 684. The pressure transducers 674,676 and thermocouples 682, 684 are coupled to electronic circuitry on anundersurface of the base 644. The electronic circuitry is coupled to thecontrol system 548 via appropriate wiring. The base 644 includes asloped surface 650 that terminates in a shoulder portion 652. The latch646 includes a corresponding catch portion 654 that is biased outwardand engages the shoulder portion 652 when the latch 646 is pivoted ontothe base 644. The latch 646 also includes a protruding release member656 that may be manipulated by a user's fingers to disengage the catchportion 654 of the latch 646 from the shoulder portion 652 of the base644.

With reference to FIGS. 69 and 70, the disposable temperature andpressure sensor block member 642 includes a polycarbonate block or base658 having first and second longitudinally extending lumens or tubes660, 662 extending therethrough. The longitudinally extending lumens660, 662 communicate with corresponding first and second pressuretransducer wells 698, 700 (FIG. 69) and first and second thermocouplewells 702, 704. The pressure transducer wells 698, 700 include centralholes 706 that communicate the respective longitudinally extendinglumens 660, 662, an inner annular raised portion 708, an outer annularrecessed portion 710, and an annular wall 712. The thermocouple wells702, 704 include central holes 714 that communicate with the respectivelongitudinally extending lumens 660, 662, an inner annular recessedportion 716, an outer annular raised portion 718, and an annular wall720.

Each pressure transducer well 698, 700 includes an O-Ring seal 686 fixedon the outer annular recessed portion 710, a pressure sensor diaphragm688 fixed on the O-Ring seal 686, over the inner annular raised portion708, and a pressure sensor bushing 690 fixed to the annular wall 712,over the diaphragm 688. Each thermocouple well 702, 704 includes anO-Ring seal 692 fixed on the inner annular recessed portion 716, asensor connection tube 694 fixed on the O-Ring seal 692 and extendinginto the central hole 714, and a temperature sensor bushing 696 fixed tothe annular wall 720, over the sensor connection tube 694.

The temperature and pressure sensor assembly 584 is assembled by fittingthe temperature and pressure block member 642 onto the temperature andpressure electronics member 640 so that the pressure transducers 674,676 and thermocouples 682, 684 of the electronics member 640 mate withthe corresponding pressure transducer wells 698, 700 and thermocouplewells 702, 704 of the block member 642. The latch 646 is then pivoted tothe locked or engaged position so that the catch portion 654 of thelatch 646 engages the shoulder portion 652 of the base 644. This locksthe block member 642 to the electronics member 640.

After a single use of the circulation set 550 or operation using thecirculation set 550, the block member 642 is preferably removed from theelectronics member 640 and disposed of. This is accomplished bydisengaging the catch portion 654 of the latch 646 from the shoulderportion 652 of the base 644 by pulling on the release member 656. Theblock member 642 along with the other disposable components of thecirculation set 550 are then disposed of. Thus, the only reusablecomponent of the pressure and temperature assembly 584 is thetemperature and pressure electronics member 640. The above-describedconstruction and configuration of the block member 642 allows for itsinexpensive manufacture, and thus, disposability, and the reusability ofthe electronics member 640 without contaminating any elements of theelectronics member 640.

As discussed infra, the air purging mechanism 604 is used to remove airfrom the lines 586, 588 and lumens 564, 566 of the system 544. Removingair from the system 544 maximizes the pressure in the system 544,maximizes heat transfer at the heat transfer element 562, and reducesthe risk of air entering the blood stream of the patient. The airpurging mechanism 604 is employed during a purge phase before each useof the system 544. The purge phase is important for identification ofthe type of catheter being used and for early detection of problems withthe system 544.

With reference to FIGS. 71 and 72, a method of automatically identifyinga catheter connected to the circulation set 550 or automaticallyidentifying a heat transfer element attached to a catheter that isconnected to a circulation set 550 based on a pressure reading in thecirculation set 550 will now be described.

FIG. 71 is a graph generally illustrating pump motor speed versus timefor exemplary purge, idle, and run cycles of the catheter system 544.The pump motor speed is representative of the fluid flow rate throughthe system 544. In the purge routine, the fluid flow rate is graduallyincreased in discrete steps.

With reference additionally to FIG. 72, each catheter 568 (e.g., 10 F,14 F, etc.) or heat transfer element 562 connected to a catheter 568 hasits own unique flow resistance, i.e., pressure versus flow response. Ifduring each discrete step of the purge cycle, both the inlet pressure ofthe catheter 568 and the pump speed are measured, a straight line may bedrawn through the measured data points and a slope computed. FIG. 72illustrates such sloped lines for a 10 F catheter and a 14 F catheterattached to the circulation set 550. The catheter 568 or heat transferelement of a catheter 568 used with the circulation set 548 may beautomatically identified by comparing the computed slope with a list ofsimilarly computed slopes obtained empirically from a set of availablecatheters. After automatically identifying the catheter being used, thecontrol system 26 may apply the corresponding optimal parameters foroperation of the catheter 568. The computed slope may also be used todetermine if a problem has occurred in the system 544, e.g., fluidleakage, if the computed slope does not match that of a specificreference catheter.

Controlling the Application of Hypothermia Background

So far Innercool has completed over 60 patients for its TCAS clinicalstudy in neurosurgery. All of the experimental patients and control wereintubated and had an esophageal temperature probe for temperaturemonitoring. Monitoring temperature in the distal esophagus has beenshown to be extremely reliable for monitoring continually coretemperature, and for providing temperature feedback for controlling theinduction and maintenance of hypothermia.

As previously mentioned, control algorithms are sometimes used tocontrol the rate at which heat is extracted from the body by thecatheter. These algorithms may be embodied in hardware, software, or acombination of both. The gain factor employed by such algorithms isdependent on the effective thermal mass of the body or organ beingcooled. Thus, it is important to determine the effective thermal mass sothat an appropriate gain factor can be calculated for the feedbackcontrol algorithm.

The mass of the body (organ or whole body) being cooled can be estimatedby relating the power removed by the catheter to the power lost by thebody.

The power removed by the catheter may be expressed as follows:

P_(catheter)=Mc_(f)ΔT  (1)

Where M is the mass flow rate of the fluid circulating through thecatheter (typically measured in terms of cc/s), c is the heat capacityof the fluid, and ΔT is the temperature difference between the workingfluid as it enters the catheter and as it exits the catheter.Accordingly, P_(catheter) can be readily calculated by measuring themass flow of the circulating fluid and the temperature differencebetween the working fluid as it enters and exits the catheter.

The power removed by the catheter as determined by equation (1) may beequated to the power that is lost by the patient's body:

P _(catheter) =mc _(b) ∂T/∂t  (2)

Where P_(catheter) is now the power lost by the pationt's body and hasthe value calculated by equation (1), m is the effective thermal mass ofthe body being cooled, c_(b) is the heat capacity of the body, and ∂T/∂tis the change in temperature per unit time of the mass being cooled.

Accordingly, the effective thermal mass of the body being cooled is:

m=P _(catheter)/(c _(b) ∂T/∂t)  (3)

Since all the variables in equation (3) are either known or aremeasurable, the effective mass can be determined.

The mass calculated in this manner is an effective thermal mass thatrepresents the portion of the body from which power is removed (i.e.,the portion of the body that is cooled). The temperature change inequation (3) represents the temperature change of the portion of thebody being cooled. For example, if whole body cooling is to beperformed, the change of the core body temperature may be measured tocalculate mass in accordance with equation (3). In general, for wholebody cooling, if the patient is vasoconstricted, the effective mass mayrepresent about 50% of the total body mass. If the patient isvasodilated, the effective mass will be closer to the total body mass.

Alternatively, if only a selected organ such as the brain is to becooled, then the temperature change that will be used in equation (3)would be the temperature change of the organ, assuming of course thatthe organ can be at least briefly considered to be largely thermallyisolated from the remainder of the body. In this case the effective massthat is determined would be comparable to the mass of the organ. If theselected organ to be cooled is the brain, for example, the catheter isplaced in the common carotid artery, the internal carotid artery, orboth. The temperature changed used in equation (3) will be measured byinserting a temperature sensor into the brain or via a tympanic membranesensor, both of which are commercially available.

EXAMPLE

In an animal study, whole body cooling was accomplished by inserting thecatheter through the femoral vein and then through the inferior venacava as far as the right atrium and the superior vena cava. Cooling wasinitiated by circulating a working fluid at a flow rate of 5 cc/sec. Thetemperature differential between the fluid entering the catheter and thefluid exiting the catheter was 17° C. Accordingly, the power extractedby the catheter was 354 watts.

The body core temperature was measured through the esophagus. Twentyminutes after cooling was initiated, the rate at which the coretemperature changed was measured over a period of about ten minutes,resulting in an average temperature change of about 4° C./hr.

From equation (3) above, the effective thermal mass is:

m=354 watts/(0.965 watts/kg·C.°)(10° C./hr)=37 kg

The total mass of the animal was 53 kg, and thus the effective mass wasfound to be 69% of the total mass.

Rewarming Strategies According to Procedure

As noted, certain applications of hypothermia have specifiedrequirements or preferences. Similarly, certain applications ofrewarming have specified requirements or preferences. These aredescribed below.

Neurosurgery

In neurosurgery, a typical goal is to rewarm the patient from ahypothermic temperature, such as about 33° C., to a slightly sub-normaltemperature, such as about 35.5° C. (core), in a short time. If therewarm rate is greater than about 2.5° C., this can be achieved in lessthan an hour. As the typical closure time is 60 minutes, this means thatrewarming can occur in the operating room, as can extubation. A neuroexam may then be performed on the conscious patient.

To accomplish this, the following protocol may be performed. Theprotocol assumes an esophageal temperature probe, although other typesof temperature probes or sensors may also be employed.

Neurosurgery Protocol

1. the patient may be draped, such as by a single or double layer.2. The bath temperature, through which the working fluid flows in orderto exchange heat, may be placed at about 50° C. Of course, sufficienttemperature drops will occur between this and the blood temperature sothat the blood temperature does not rise beyond 42° C.3. The target temperature for the control system may be programmed atabout 35.5° C.4. After achieving target temperature, the patient may be moved to aPACU/ICU and rewarmed using prior art warming techniques, such asconvective air blankets, etc.

Stroke

In stroke, a typical goal is to rewarm the patient gradually from ahypothermic temperature, such as about 33° C., to a “normal”temperature, such as about 36.5° C. (core), over an extended period oftime, such as about 12 to 24 hours. The ICP is preferably minimized inits rebound, and patient comfort is maintained, without a shivering orcold sensation. To accomplish this, the following protocol may beperformed. The protocol assumes a bladder temperature probe, althoughother types of temperature probes or sensors may also be employed.

Stroke Protocol

1. The patient may be warmed by active surface warming, such as at about41° C., to prevent shivering. This warming can be provided by electricblanket or convective air blanket.2. The console may then provide a controlled rewarm to match the targettemperature ramp function. In other words, a preferred ramp value may beinput by the caregiver, this ramp being the rate at which the patient isto be rewarmed. The controller in the console then matches the true ratewith this programmed ramp. The ramp would be determined by the amount oftime over which the physician wishes the patient's temperature to rise,as well as the amount of rise needed to reach normothermia or apre-normothermia temperature, such as 36.5° C.3. The patient may be administered an anti-shivering drug, such asmeperidine.4. After achieving target temperature, the patient may be moved to aPACU/ICU and rewarmed using prior art warming techniques, such asconvective air blankets, etc.

Cardiovascular Surgery

In cardiovascular surgery, a typical goal is to maintain normothermia inthe initial perioperative period following separation fromcardiopulmonary bypass (CPB) until, e.g., the first 24 hours after theoperation. In this regime, it would be desirable to rewarm and maintainthe patient's temperature at least about 36° C. in the operating roomduring the last 30 to 45 minutes of closing. Complicating this is thatdisconnecting from the CPB pump usually yields an after drop of 1 to 2°C. due to redistribution and further heat loss to the environment. It ispreferred to not have to use active surface warming during closure, orin the ICU.

To accomplish this, the following protocol may be performed. Theprotocol assumes an esophageal temperature probe or that of a PAcatheter, although other types of temperature probes or sensors may alsobe employed.

Cardiovascular Surgery Protocol

1. The heat transfer element and catheter are inserted at the beginningof the case.2. The CV procedure is performed.3. Once the patient is off the pump, the system is started in rewarmingmode and the patient target temperature is set to 36.5° C.4. When desired or appropriate, or after patient reaches the targettemperature, the catheter may be disconnected from the console in orderto transport patient to the ICU.5. The patient may then be reconnected to the console and rewarmingcontinued, along with prior art warming techniques, such as convectiveair blankets, etc.6. Normothermia maintenance may be continued for the next 24 hours orfor a time period determined by the physician.

Method of Making the Heat Transfer Element

The method of manufacturing a heat transfer element will now bedescribed in more detail. The exterior structure of the heat transferelement is of a complex shape as has been described in order to inducemixing in the flow of blood around the heat transfer element, as well asto induce mixing in the flow of working fluid within the heat transferelement. As may be clear, many varieties and shapes may be employed tocause such flow. Such shapes are termed herein as “mixing-inducingshapes”. Examples of mixing-inducing shapes include: helical,alternating helical or other enantiomorphic shapes, aberration-includingshapes, bump-including shapes, channel-including shapes, crenellatedshapes, hook- or horn-shapes, labyrinthine shapes, and any other shapescapable of inducing mixing. Thus, the metallic element or elements orcompounds forming the heat transfer element must be sufficiently ductileto assume such shapes during deposition.

It is further noted here that while the generic term “deposition” isused, this term is intended broadly to cover any process in which metalsor coating may be disposed on a mandrel or other layer of a heattransfer element. For example, deposition may include: CVD, PVD,sputtering, MBE, forms of crystal or amorphic material “growth”, spraycoating, electroplating, ECD, and other methods which may be employed toform a mandrel or a coating having a mixing-inducing shape. Methods suchas ECD and electroplating have the benefit of having a chargedworkpiece—this charge may be employed to fix the workpiece to the tool.

In general, the processes which may be employed to form the heattransfer element include forming a mandrel having a mixing inducingshape, coating the mandrel with a metal layer or a series of layers(i.e., the heat transfer element), and dissolving the mandrel.

A first step in the process of forming a heat transfer element may be toform a mandrel. One type of mandrel may be made of aluminum such as Al6061 with a T6 heat treatment. Aluminum is useful because the same iscapable of being dissolved or leached out easily with a caustic soda. Ahole disposed along the axis of the heat transfer element may speed suchleaching. The mandrel may be formed by machining such as by a CitizenSwiss Screw Machine. The mandrel may also be made via injection moldingif the same is made of plastic, wax, low-melting-temperaturethermoplastics, and the like. Other methods which may be employed toform the mandrel include machining via laser (note that laser forming istypically only employed for the outside of an element), hydroforming,and other similar methods.

However the mandrel is formed, it is important for the same to have asmooth surface finish and exterior texture. In this way, the resultingheat transfer element will be smooth. A smooth mandrel allows anatraumatic device to be formed around the same. A smooth mandrel alsoallows a smooth metallic coating (heat transfer element) to be simplydeposited around the same thus ensuring uniform heat transfer, aconstant thickness of biocoating, an atraumatic profile, etc.

A basic series of coating layers is shown in FIG. 73. FIG. 73 shows amechanical layer 724, typically made of a metal, and a biocompatiblelayer 726. The mechanical layer 724 is the basic conductive element. Themechanical layer 724 is responsible for heat conduction to providecooling and thus should have a thermal conductivity in the range ofabout 0.1 to 4 W/cm-K, so long as such materials can be deposited.Typical metals which may be employed for the mechanical layer 724include Ni, Cu, Au, Ag, Ti, Ta, nitinol, stainless steel, etc. orcombinations of these or other similar elements. The thickness of themechanical layer should be less than about 2 mils thick to allow forsufficient flexibility to navigate tortous vasculature, although this isstrongly dependent on the type of metal and on the tortuousity of thevasculature involved. Regarding the type of metal, any noble metal maybe employed. Certain of these have deleterious biocompatibility,however, and each has different manufacturing concerns. For example, aAu heat transfer element would require a seed layer since Au will notstick to the Al mandrel.

Ni has been found to be useful. Cu is also useful and has a highconductivity; unfortunately, Cu is also likely to assume the form of thevasculature in which the same is disposed.

For sake of argument, it is assumed here that Ni forms the basic heattransfer element. As stated above, Ni is not hemocompatible. Thus, abiocompatible layer 726 is disposed on the mechanical layer 724 as isshown in FIG. 73. The biocompatible layer may be, e.g., urethane,parylene, Teflon®, a lubricious coating, an antithrombogenic coatingsuch as heparin, a noble metal such as Au, or combinations of the aboveor other similar materials.

One difficulty with the above embodiment may be that, with use ofcertain working fluids, such as saline, corrosion of the mechanicallayer may occur. In the case of a mechanical layer 724 of Ni, saline maybe especially corrosive. Thus, a protective layer 722 may be employedthat is noncorrosive with respect to saline. For example, the protectivelayer 722 may be made of Au. A Au protective layer 722 may encounterdifficulties attaching to an aluminum mandrel, and thus if necessary alayer of Cu may be deposited on the mandrel prior to deposition of theAu layer. Following the dissolution of the mandrel, the Cu layer mayalso be etched away. The protective layer may generally be any noble orinert metal, or may be a polymer or other protective material such asTeflon®.

Alternatively, the protective layer 722 may be vacuum deposited, such asby a vapor deposition method, following removal or dissolution of themandrel. The resulting hole left by the dissolved mandrel allows a pathfor vaporized gases or liquid chemicals to flow. Thus, materials can bedeposited in this fashion on the inside of the heat transfer element.The materials so deposited may be the same as those discussed above:polymers, such as non-corrosive or non-polar polymers, noble metals, andthe like.

FIG. 74 also shows two layers above the mechanical layer 724: abiocompatible layer 726 and a heparin/lubricious layer 728. These mayalso be combined to form a single biocompatible layer. Alternatively,the biocompatible layer may be a “seed” layer which enhances theconnection of the heparin/lubricious layer 728 to the underlyingmechanical layer 724. Such a seed layer may be, e.g., parylene. Finally,it should be noted that the heparin/lubricious layer 728 is indicated asexemplary only: either heparin or a lubricious layer may be depositedindividually or in combination. For example, in certain applications,heparin may not be necessary.

Another embodiment is shown in FIG. 75. This embodiment addressesanother difficulty that may occur with various metals. For example, amechanical layer 724 that is made entirely of Ni may have too low aburst pressure, partially due to its porosity. The protective layer 722of FIG. 74 may address some of these concerns. A better approach may bethat shown in FIG. 75. In FIG. 75, the mechanical layer 724 is broken upinto several layers. Two, three, or more layers may be employed. In FIG.75, layers 724 a and 724 c are formed of a first material such as Ni. Aninterior layer 724 b is deposited between layers 724 a and 724 c. Thislayer 724 b may be formed of a second material such as Cu. Thiscombination of layers 724 a, 724 b, and 724 c forms a mechanical“sandwich” structure. The Cu layer 724 b (the second “metal” or “layer”)may serve to close “pinholes” that may exist within the more porous Nilayers 724 a and 724 c (the first “metal” or “layer”).

One embodiment that has been found useful is that described by Table Ibelow. In Table I, the biocompatible coating is a noble metal layer ofAu. It should be noted that Table I describes a very specific embodimentand is provided purely for illustrative purposes. Table I should not beconstrued as limiting. Table I is keyed to FIG. 75.

Layer Number Material Thickness 102 Au (e.g., mil-g-45204, type 1/10 milone, grade A, class one) 104a Ni 3½/10 to 1 mil 104b Cu 1/10 mil 104c Ni3½/10 to 1 mil 106 Au 1/10 mil 108 heparin/lubricious 7-10 microns

The overall thickness of the group of layers 102-108 may be about 1 mil.The nickel and copper may contain traces of other elements withoutdeleterious consequences.

While the particular invention as herein shown and disclosed in detailis fully capable of obtaining the objects and providing the advantageshereinbefore stated, it is to be understood that this disclosure ismerely illustrative of the presently preferred embodiments of theinvention and that no limitations are intended other than as describedin the appended claims.

1-3. (canceled)
 4. A method of rewarming a patient following a strokecomprising: covering a patient with a heating blanket set to atemperature of between about 38° C. and 43° C.; inserting a heattransfer element into a vein of the patient; circulating a working fluidthrough the heat transfer element; sensing a patient temperature;controlling the patient temperature such that the patient temperaturerises to greater than about 36° C. over a period of time between about 6hours to about 24 hours; if the patient is experiencing shivering duringthe controlled rewarm, administering an antishivering drug; andrewarming the patient to normothermia using the active heating blanket,wherein the heat transfer element includes a straight lumen surroundedby a helical lumen.
 5. The method of claim 4, wherein the heat transferelement is flexible and is made of a polymer.
 6. A method of rewarming apatient following a stroke, comprising: covering a patient with aheating blanket set to a temperature of between about 38° C. and 43° C.;inserting a heat transfer element into a vein of the patient;circulating a working fluid through the heat transfer element; sensing apatient temperature; controlling the patient temperature such that thepatient temperature rises to greater than about 36° C. over a period oftime between about 6 hours to about 24 hours; if the patient isexperiencing shivering during the controlled rewarm, administering anantishivering drug; and rewarming the patient to normothermia using theactive heating blanket, wherein the anti-shivering drug is meperidine.7. The method of claim 6, wherein the sensing a patient temperatureincludes sensing a patient temperature with an esophageal probe.
 8. Themethod of claim 6, wherein the sensing a patient temperature includessensing a patient temperature with a bladder probe.
 9. A method ofrewarming a patient following a cardiovascular surgery, comprising:inserting a heat transfer element into a vein of the patient; performinga cardiac surgery; following the cardiac surgery, circulating a workingfluid through the heat transfer element, the working fluid heated by aheat exchanger to a temperature sufficient to raise the bloodtemperature to a blood temperature less than about 42° C.; sensing apatient temperature; controlling the patient temperature such that thepatient temperature rises to greater than about 36.5° C.
 10. The methodof claim 9, wherein the heat transfer element is flexible and is made ofmetal.
 11. The method of claim 10, wherein the heat transfer elementincludes at least two heat transfer segments separated by a bellows. 12.The method of claim 9, wherein the heat transfer element is a balloon.13. The method of claim 12, wherein the heat transfer element includes astraight lumen surrounded by a helical lumen.
 14. The method of claim13, wherein the heat transfer element includes a straight lumensurrounded by at least two helical lumens.
 15. The method of claim 9,wherein the sensing a patient temperature includes sensing a patienttemperature with an esophageal probe.
 16. The method of claim 9, whereinthe sensing a patient temperature includes sensing a patient temperaturewith a bladder probe.